U.S. patent number 9,944,658 [Application Number 14/773,717] was granted by the patent office on 2018-04-17 for beta-lactamase inhibitors.
This patent grant is currently assigned to VENATORX PHARMACEUTICALS, INC.. The grantee listed for this patent is VenatoRx Pharmaceuticals, Inc.. Invention is credited to Christopher J. Burns, Denis Daigle, Bin Liu, Daniel McGarry, Daniel C. Pevear, Robert E. Lee Trout.
United States Patent |
9,944,658 |
Burns , et al. |
April 17, 2018 |
**Please see images for:
( Certificate of Correction ) ** |
Beta-lactamase inhibitors
Abstract
Described herein are compounds and compositions that modulate
the activity of beta-lactamases. In some embodiments, the compounds
described herein inhibit beta-lactamase. In certain embodiments,
the compounds described herein are useful in the treatment of
bacterial infections.
Inventors: |
Burns; Christopher J. (Malvern,
PA), Daigle; Denis (Street, MD), Liu; Bin (Dayton,
NJ), McGarry; Daniel (Malvern, PA), Pevear; Daniel C.
(Downingtown, PA), Trout; Robert E. Lee (Collegeville,
PA) |
Applicant: |
Name |
City |
State |
Country |
Type |
VenatoRx Pharmaceuticals, Inc. |
Malvern |
PA |
US |
|
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Assignee: |
VENATORX PHARMACEUTICALS, INC.
(Malvern, PA)
|
Family
ID: |
51581080 |
Appl.
No.: |
14/773,717 |
Filed: |
March 13, 2014 |
PCT
Filed: |
March 13, 2014 |
PCT No.: |
PCT/US2014/026727 |
371(c)(1),(2),(4) Date: |
September 08, 2015 |
PCT
Pub. No.: |
WO2014/151958 |
PCT
Pub. Date: |
September 25, 2014 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20160024121 A1 |
Jan 28, 2016 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61785919 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F
5/025 (20130101); A61K 45/06 (20130101); A61K
31/69 (20130101); Y02A 50/483 (20180101); Y02A
50/475 (20180101); Y02A 50/473 (20180101); Y02A
50/30 (20180101) |
Current International
Class: |
C07F
5/02 (20060101); A61K 45/06 (20060101); A61K
31/69 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO-2005004799 |
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Jan 2005 |
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WO |
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WO-2009064413 |
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May 2009 |
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WO |
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WO-2009064414 |
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May 2009 |
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WO |
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WO-2010056827 |
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May 2010 |
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WO |
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WO-2010130708 |
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Nov 2010 |
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WO |
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WO-2012021455 |
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Feb 2012 |
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WO |
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WO-2013053372 |
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Apr 2013 |
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WO |
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WO-2013092979 |
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Jun 2013 |
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WO |
|
WO-2013122888 |
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Aug 2013 |
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WO |
|
WO-2014089365 |
|
Jun 2014 |
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WO |
|
WO-2014107535 |
|
Jul 2014 |
|
WO |
|
WO-2014107536 |
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Jul 2014 |
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WO |
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WO-2014110442 |
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Jul 2014 |
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WO |
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WO-2014151958 |
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Sep 2014 |
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WO |
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WO-2014151959 |
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Sep 2014 |
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WO |
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Other References
Patani et al. Bioisosterism: A Rational Approach in Drug Design.
Chemical Reviews 96:3147-3176 (1996). cited by applicant .
Co-pending U.S. Appl. No. 15/194,443, filed Jun. 27, 2016. cited by
applicant .
Co-pending U.S. Appl. No. 15/212,959, filed Jul. 18, 2016. cited by
applicant .
Co-pending U.S. Appl. No. 15/261,359, filed Sep. 9, 2016. cited by
applicant .
Burns et al. CAPLUS AN 2014-1130723 (2014). cited by applicant
.
Isomer. https://en.wikipedia.org/wiki/Isomer (2015). cited by
applicant .
PCT/US2015/035407 International Search Report and Written Opinion
dated Oct. 20, 2015. cited by applicant .
U.S. Appl. No. 14/649,527 Office Action dated Nov. 9, 2015. cited
by applicant .
U.S. Appl. No. 14/759,853 Office Action dated Dec. 11, 2015. cited
by applicant .
Bodner Research Web. The Chemistry of the Halogens. Available from
http://web.archive.org/web/20090414155348/http://chemechem/topicreview/bp-
/ch10/group3.php. cited by applicant .
Co-pending U.S. Appl. No. 14/649,527, filed Jun. 3, 2015. cited by
applicant .
Co-pending U.S. Appl. No. 14/736,921, filed Jun. 11, 2015. cited by
applicant .
Co-pending U.S. Appl. No. 14/737,156, filed Jun. 11, 2015. cited by
applicant .
Co-pending U.S. Appl. No. 14/737,323, filed Jun. 11, 2015. cited by
applicant .
Co-pending U.S. Appl. No. 14/759,853, filed Jul. 8, 2015. cited by
applicant .
Eidam et al. Design, synthesis, crystal structures, and
antimicrobial activity of sulfonamide boronic acids as
.beta.-lactamase inhibitors. J. Med. Chem. 53(21):7852-7863 (2010).
cited by applicant .
Ettmayer et al. Lessons Learned from Marketed and Investigational
Prodrugs. J Medicinal Chem. 47(10):2393-2404. 2004. cited by
applicant .
Han. Targeted Prodrug Design to Optimize Drug Delivery. AAPS
Pharmsci. 2(1)Article 6:1-11 (2000). cited by applicant .
Lima et al. Bioisosterism: A Useful Strategy for Molecular
Modificaion and Drug Design. Current Medicinal Chemistry 12:23-49
(2005). cited by applicant .
Morandi et al. Structure-based optimization of cephalothin-analogue
boronic acids as .beta.-lactamase inhibitors. Bioorg. Med. Chem.
16(3):1195-1205 (2008) (Epub: Nov. 7, 2007). cited by applicant
.
Ness et al. Structure-based design guides the improved efficacy of
deacylation transition state analogue inhibitors of TEM-1
.beta.-lactamase. Biochemistry 39(18):5312-5321 (2000). cited by
applicant .
PCT/US2013/073428 International Search Report dated Apr. 25, 2014.
cited by applicant .
PCT/US2014/011144 International Search Report dated May 12, 2014.
cited by applicant .
PCT/US2014/026727 International Search Report and Written Opinion
dated Jul. 25, 2014. cited by applicant .
Powers et al. Structure-based approach for binding site
identification on AmpC .beta.-lactamase. J. Med. Chem.
45(15):3222-3234 (2002). cited by applicant .
Powers et al. Structures of ceftazidime and its transition-state
analogue in complex with AmpC .beta.-lactamase: implications for
resistance mutations and inhibitor design. Biochemistry
40(31):9207-9214 (2001). cited by applicant .
Testa. Prodrug research: futile or fertile? Biochem. Pharm.
68:2097-2106 (2004). cited by applicant .
U.S. Appl. No. 14/693,318 Office Action dated Sep. 1, 2015. cited
by applicant .
U.S. Appl. No. 14/152,916 Office Action dated Aug. 29, 2014. cited
by applicant .
Weston et al. Structure-based enhancement of boronic acid-based
inhibitors of AmpC .beta.-lactamase. J. Med. Chem. 41(23):4577-4586
(1998). cited by applicant .
Bacterial Infection 101. Available at
http://www.onhealth.com/content/l/bacterial_infections (34 pgs)
(2017). cited by applicant .
Definition of Quinoxaline from PubChem.
http://pubchem.ncbi.nlm.nih.gov/compund/quinoxaline#section=information-s-
ources. (24 pgs) (2005). cited by applicant .
Definition of Quinoxaline from Wikipedia.
http://en.wikipedia.org/wiki/Quinoxaline (3 pgs.) (2016). cited by
applicant .
Ishikawa et al. Synthesis and antimicrobial activity of
2,3-bis(bromomethyl)quinoxaline derivatives. Bioorg Chem 41-42:1-5
(2012). cited by applicant .
Pub Chem Substance Record for SID 197433672.
https://pubchem.ncbi.nim.nih/substance/197433672. Created Aug. 18,
2014. Retrieved Jan. 10, 2017 ( 5 pgs). cited by applicant .
U.S. Appl. No. 15/194,433 Office Action dated Feb. 9, 2017. cited
by applicant .
U.S. Appl. No. 15/212,959 Office Action dated Mar. 23, 2017. cited
by applicant .
U.S. Appl. No. 90/013,866 Ex Parte Reexam Office Action dated Apr.
20, 2017. cited by applicant .
Isomer. https://en.wikipedia.org/wiki/Isomer (5 pgs) (2017). cited
by applicant.
|
Primary Examiner: Kosack; Joseph R
Attorney, Agent or Firm: Wilson, Sonsini, Goodrich &
Rosati
Government Interests
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
This invention was made with the support of the United States
government under Contract numbers R43AI096679 by National
Institutes of Health (NIH), R43AI096613 by National Institutes of
Health (NIH), and R01AI089512 by National Institutes of Health
(NIH). The government has certain rights in the invention.
Parent Case Text
CROSS-REFERENCE
This application is a U.S. National Stage entry of International
Application No. PCT/US14/26727, filed Mar. 13, 2014, which claims
the benefit of priority from U.S. provisional application Ser. No.
61/785,919, filed Mar. 14, 2013, all of which are incorporated
herein by reference in their entirety.
Claims
What is claimed is:
1. A compound of Formula (I) or Formula (Ia), a pharmaceutically
acceptable salt, polymorph, solvate, prodrug, N-oxide, or
stereoisomer thereof: ##STR00194## wherein: M is a bond; m is 0, 1,
or 2; provided that when HetA is attached to
(CR.sup.1R.sup.2).sub.m through a ring nitrogen atom, m=0 or 2; n
is 0, 1, 2, or 3; provided that m or n is 1; p is 0,1,2,3 or 4;
X.sup.1 and X.sup.2 are independently selected from --OH,
--OR.sup.8, or F; Z is >C.dbd.0, >C.dbd.S, or >SO.sub.2;
HetA is an optionally substituted non-aromatic heterocyclic ring
system; Y is selected from the group consisting fluoro, chloro,
--CN, optionally substituted C.sub.1-C.sub.6 alkyl, --OH,
--OR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5, --C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.4C(.dbd.NR.sup.4)NR.sup.-
4R.sup.5, --NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.vHeteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl, and
--O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl; v is 1-4; w is 2-4;
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --NR.sup.4R.sup.5, and --SR.sup.10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, fluoro, chloro, bromo, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, --OH, --OR.sup.10, --SR.sup.10, and --NR.sup.4R.sup.5,
or R.sup.1 and R.sup.2 taken together form an oxo, oxime, or an
optionally substituted carbocycle or optionally substituted
heterocycle with the carbon to which they are attached; R.sup.3 is
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or a
pharmaceutically acceptable prodrug; R.sup.d, R.sup.4 and R.sup.5
are independently selected from the group consisting of hydrogen,
--OH, --CN, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted aminoalkyl, optionally
substituted cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an
optionally substituted saccharide; or R.sup.4 and R.sup.5 taken
together form an optionally substituted heterocycle with the
nitrogen to which they are attached; R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
fluoro, chloro, bromo, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5,
--NR.sup.4SO.sub.2R.sup.5, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl;
or R.sup.6 and R.sup.7 taken together form an oxo, oxime, or an
optionally substituted carbocycle or an optionally substituted
heterocycle with the carbon to which they are attached; R.sup.8 is
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, or a pharmaceutically
acceptable boronate ester group; R.sup.9 is optionally substituted
C.sub.1-C.sub.6 alkyl; and R.sup.10 is optionally substituted
C.sub.1-C.sub.6 alkyl or optionally substituted C.sub.3-C.sub.6
cycloalkyl.
2. The compound of claim 1, wherein R.sup.a, R.sup.b, and R.sup.c
are independently hydrogen, fluoro, or chloro.
3. The compound of claim 1, wherein R.sup.a, R.sup.b, and R.sup.c
are hydrogen.
4. The compound of claim 1, wherein R.sup.3 is hydrogen.
5. The compound of claim 1, wherein X.sup.1 and X.sup.2 are
--OH.
6. The compound of claim 1, wherein R.sup.d is hydrogen or
C.sub.1-C.sub.4-alkyl.
7. The compound of claim 1, wherein Z is >C.dbd.O.
8. The compound of claim 1, wherein HetA is selected from the group
consisting of azetidine, oxetane thietane, pyrrolidine oxazolidine,
isoxazolidine, thiazolidine, isothiazolidine, imidazolidine,
pyrazolidine, 2,5-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyrrole,
4,5-dihydrooxazole, 4,5-dihydroisoxazole, 4,5-dihydrothiazole,
4,5-dihydroisothiazole, 4,5-dihydro-1H-pyrazole,
4,5-dihydro-1H-imidazole, 2,5-dihydro-1H-pyrrole, piperidine,
morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydropyran,
tetrahydrofuran, 1,4-oxathiane, piperazine, hexahydropyrimidine,
hexahydropyridazine, 1,4,5,6-tetrahydropyrimidine, 1,3-oxazinane,
5,6-dihydro-4H-1,3-oxazine, 1,3-thiazinane,
5,6-dihydro-4H-1,3-thiazine, 1,4,5,6-tetrahydropyridazine,
1,2,3,6-tetrahydropyrazine, 1,2,3,6-tetrahydropyridine,
1,2,3,6-tetrahydropyridazine, azepane, 1,3-oxazepane,
1,4-oxazepane, 1,3-diazepane, 1,4-diazepane, 1,3-thiazepane,
1,4-thiazepane, diazepane, oxazepane, thiazepane,
3,4,5,6-tetrahydro-2H-azepine, 4,5,6,7-tetrahydro-1H-1,3-diazepine,
4,5,6,7-tetrahydro-1,3-oxazepine,
4,5,6,7-tetrahydro-1,3-thiazepine,
2,3,4,7-tetrahydro-1H-1,3-diazepine, and
2,3,4,7-tetrahydro-1,3-oxazepine.
9. The compound of claim 8, wherein HetA is selected from the group
consisting of piperidine, piperazine, pyrrolidine, tetrahydropyran,
and tetrahydrofuran.
10. The compound of claim 1, wherein Y is selected from the group
consisting fluoro, chloro, --CN, optionally substituted
C.sub.1-C.sub.6 alkyl, --OH, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5, --C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6,
--NR.sup.4C(O)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)-Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl, and
--NR.sup.4(CR.sup.6R.sup.7).sub.v-Heterocyclyl.
11. The compound of claim 1, wherein Y is selected from the group
consisting of --NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
NR.sup.5C(.dbd.NR.sup.5)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--NR.sup.5C(O)CR.sup.6(NR.sup.4R.sup.5)(CR.sup.6R.sup.7).sub.vNR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5, --C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5.
12. The compound of claim 1, wherein p is 1 or 2.
13. The compound of claim 1, wherein R.sup.4 and R.sup.5 are
independently hydrogen or optionally substituted C.sub.1-C.sub.6
alkyl.
14. The compound of claim 1, wherein R.sup.6 and R.sup.7 are
independently hydrogen, fluoro, or optionally substituted
C.sub.1-C.sub.6 alkyl.
15. The compound of claim 1, wherein the compound is selected from
the group represented by the following structures: ##STR00195##
##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200##
##STR00201## ##STR00202## ##STR00203## ##STR00204## or a
pharmaceutically acceptable salt, polymorph, solvate, prodrug,
N-oxide, or stereoisomer thereof, wherein the compound is present
in a closed, cyclic form according to Formula (I) and as shown in
the structures above, in an open, acyclic form according to Formula
(Ia), or mixtures thereof.
16. A pharmaceutical composition comprising a compound of claim 1
or a pharmaceutically acceptable salt, polymorph, solvate, prodrug,
N-oxide, or stereoisomer thereof, and a pharmaceutically acceptable
excipient.
17. The pharmaceutical composition of claim 16, further comprising
a beta-lactam antibiotic.
18. The pharmaceutical composition of claim 17, wherein the
beta-lactam antibiotic is a penicillin, cephalosporin, carbapenem,
monobactam, bridged monobactam, or a combination thereof.
19. A method of treating a bacterial infection in a subject,
comprising administering to the subject a pharmaceutical
composition of claim 16, optionally in combination with a
beta-lactam antibiotic.
Description
FIELD OF INVENTION
The present invention relates to boron-containing compounds,
compositions, preparations and their use as inhibitors of
beta-lactamase enzymes and as antibacterial agents.
BACKGROUND OF THE INVENTION
Antibiotics are the most effective drugs for curing
bacteria-infectious diseases clinically. They have a wide market
due to their advantages of good antibacterial effect with limited
side effects. Among them, the beta-lactam class of antibiotics (for
example, penicillins, cephalosporins, and carbapenems) are widely
used because they have a strong bactericidal effect and low
toxicity.
To counter the efficacy of the various beta-lactams, bacteria have
evolved to produce variants of beta-lactam deactivating enzymes
called beta-lactamases, and in the ability to share this tool
inter- and intra-species. These beta-lactamases are categorized as
"serine" or "metallo" based, respectively, on presence of a key
serine or zinc in the enzyme active site. The rapid spread of this
mechanism of bacterial resistance can severely limit beta-lactam
treatment options in the hospital and in the community. Currently
available beta-lactamase inhibitors (for example, clavulanic acid
and tazobactam) are poorly active against the diversity of
beta-lactamase enzymes (both serine- and metallo-based) now
emerging clinically. There is an urgent need for new beta-lactamase
inhibitors with broadened enzyme spectrum.
SUMMARY OF THE INVENTION
Described herein are compounds that modulate the activity of
beta-lactamases. In some embodiments, the compounds described
herein inhibit beta-lactamases. In certain embodiments, the
compounds described herein are useful in the treatment of bacterial
infections.
In one aspect, provided herein are compounds of Formula I or
Formula Ia, or pharmaceutically acceptable salts, polymorphs,
solvates, tautomers, metabolites, or N-oxides thereof:
##STR00001## wherein: M is a bond, --O--, --S--, --S(O)--,
SO.sub.2--, or --N(R.sup.4)--; m is 0, 1, or 2; provided that when
HetA is attached to (CR.sup.1R.sup.2).sub.m through a ring nitrogen
atom, m=0 or 2. n is 0, 1, 2, or 3; provided that when n is 0, then
M is a bond; p is 0, 1, 2, 3 or 4; X.sup.1 and X.sup.2 are
independently selected from --OH, --OR.sup.8, or F; Z is
>C.dbd.O, >C.dbd.S, or >SO.sub.2; HetA is an optionally
substituted non-aromatic heterocyclic ring system; Each Y, provided
Y is not attached directly to a heteroatom of HetA, is selected
from the group consisting of: fluoro, chloro, bromo, --CN,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted
heterocycle, optionally substituted aryl, optionally substituted
heteroaryl, --OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)
(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--NR.sup.4(CR.sup.6R.sup.7).sub.vS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5) R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4-
R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.-
4R.sup.5,
--S(O).sub.0,1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.-
5C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -Heteroaryl-NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.v Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl,
--NR.sup.4R.sup.5R.sup.9+Q.sup.-.sub.2,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.s-
ub.2, --(CR.sup.6R.sup.7).sub.v(T).sup.+Q.sup.-, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-; wherein:
T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; or two Ys
taken together with the carbon atoms to which they are attached
form an optionally substituted carbocycle, an optionally
substituted heterocycle, or a carbonyl group; or in the case where
Y is attached directly to a heteroatom of HetA, Y is selected from
the group consisting of: --(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(O)(CR.sup.6R.sup.7)).sub.wNR.sup.4R.-
sup.5,
--(CR.sup.6R.sup.7).sub.wNR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.s-
up.5, --NR.sup.4(CR.sup.6R.sup.7).sub.wOR.sup.10,
--(CR.sup.6R.sup.7).sub.wS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--S(O).sub.1,2NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.-
sup.5, --C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--S(O).sub.1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(-
.dbd.NR.sup.4)NR.sup.4R.sup.5, --C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --SO.sub.2R.sup.6,
--C(O)R.sup.6, --C(.dbd.O)OR.sup.6, --C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -aryl, -heteroaryl,
--C(O)N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5,
--C(O)N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4) C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--(CR.sup.6R.sup.7).sub.vO-Heterocyclyl, --R.sup.9+Q.sup.-,
--(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.sub.2
and --(CR.sup.6R.sup.7).sub.v(T).sup.+Q; wherein: T is
pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; w is 2-4;
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --NR.sup.4R.sup.5, and --SR.sup.10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, fluoro, chloro, bromo, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, --OH, --OR.sup.10, --SR.sup.10, and --NR.sup.4R.sup.5,
or R.sup.1 and R.sup.2 taken together form an oxo, oxime, or an
optionally substituted carbocycle or optionally substituted
heterocycle with the carbon to which they are attached; R.sup.3 is
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or a
pharmaceutically acceptable prodrug; R.sup.d, R.sup.4 and R.sup.5
are independently selected from the group consisting of hydrogen,
--OH, --CN, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted aminoalkyl, optionally
substituted cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an
optionally substituted saccharide; or R.sup.4 and R.sup.5 taken
together form an optionally substituted heterocycle with the
nitrogen to which they are attached; R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
fluoro, chloro, bromo, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5,
--NR.sup.4SO.sub.2R.sup.5, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl;
or R.sup.6 and R.sup.7 taken together form an oxo, oxime, or an
optionally substituted carbocycle or an optionally substituted
heterocycle with the carbon to which they are attached; R.sup.8 is
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, or a pharmaceutically
acceptable boronate ester group; R.sup.9 is optionally substituted
C.sub.1-C.sub.6 alkyl; and R.sup.10 is optionally substituted
C.sub.1-C.sub.6 alkyl or optionally substituted C.sub.3-C.sub.6
cycloalkyl.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, --OH, --OR.sup.10, --NR.sup.4R.sup.5,
and --SR.sup.10. In certain embodiments, R.sup.a, R.sup.b, and
R.sup.c are independently hydrogen, fluoro, or chloro. In preferred
embodiments, R.sup.a, R.sup.b, and R.sup.c are hydrogen.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.3 is hydrogen, methyl, ethyl, propyl, butyl, or isopropyl. In
preferred embodiments, R.sup.3 is hydrogen.
In some embodiments of a compound of Formula I or Formula Ia,
X.sup.1 and X.sup.2 are --OH.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.d is hydrogen or C.sub.1-C.sub.4-alkyl. In preferred
embodiments, R.sup.d is hydrogen.
In some embodiments of a compound of Formula I or Formula Ia, Z is
>C.dbd.O or >SO.sub.2. In preferred embodiments, Z is
>C.dbd.O.
In some embodiments of a compound of Formula I or Formula Ia, HetA
is selected from the group consisting of azetidine, oxetane
thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,
oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,
imidazolidine, pyrazolidine, 2,5-dihydro-1H-pyrrole,
3,4-dihydro-2H-pyrrole, 4,5-dihydrooxazole, 4,5-dihydroisoxazole,
4,5-dihydrothiazole, 4,5-dihydroisothiazole,
4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-imidazole,
2,5-dihydro-1H-pyrrole, piperidine, morpholine, thiomorpholine,
tetrahydrothiopyran, tetrahydropyran, 1,4-oxathiane, piperazine,
hexahydropyrimidine, hexahydropyridazine,
1,4,5,6-tetrahydropyrimidine, 1,3-oxazinane,
5,6-dihydro-4H-1,3-oxazine, 1,3-thiazinane,
5,6-dihydro-4H-1,3-thiazine, 1,4,5,6-tetrahydropyridazine,
1,2,3,6-tetrahydropyrazine, 1,2,3,6-tetrahydropyridine,
1,2,3,6-tetrahydropyridazine, 1,2,3,6-tetrahydropyridine,
3,6-dihydro-2H-pyran, 3,6-dihydro-2H-thiopyran, azepane,
1,3-oxazepane, 1,4-oxazepane, 1,3-diazepane, 1,4-diazepane,
1,3-thiazepane, 1,4-thiazepane, diazepane, oxazepane, thiazepane,
3,4,5,6-tetrahydro-2H-azepine, 4,5,6,7-tetrahydro-1H-1,3-diazepine,
4,5,6,7-tetrahydro-1,3-oxazepine,
4,5,6,7-tetrahydro-1,3-thiazepine,
2,3,4,7-tetrahydro-1H-1,3-diazepine,
2,3,4,7-tetrahydro-1,3-oxazepine, 2,3,4,7-tetrahydro-1H-azepine,
2,3,6,7-tetrahydro-1H-azepine, oxepane, thiepane,
2,3,6,7-tetrahydrooxepine, 2,3,4,7-tetrahydrooxepine,
2,3,4,7-tetrahydrothiepine, 2,3,6,7-tetrahydrothiepine azocane,
oxocane, thiocane, 1,3-diazocane, 1,4-diazocane, 1,5-diazocane,
1,3-oxazocane, 1,4-oxazocane, 1,5-oxazocane, 1,3-thiazocane,
1,4-thiazocane, 1,5-thiazocane,
(2Z)-1,4,5,6,7,8-hexahydro-1,3-diazocine,
(3Z)-1,2,5,6,7,8-hexahydro-1,4-diazocine,
(5Z)-1,2,3,4,7,8-hexahydro-1,5-diazocine,
(6Z)-1,2,3,4,5,8-hexahydro-1,3-diazocine,
(4Z)-1,2,3,6,7,8-hexahydro-1,4-diazocine,
(6Z)-1,2,3,4,5,8-hexahydroazocine,
(5Z)-1,2,3,4,7,8-hexahydroazocine,
(6Z)-3,4,5,8-tetrahydro-2H-oxocine,
(5Z)-3,4,7,8-tetrahydro-2H-oxocine,
(6Z)-3,4,5,8-tetrahydro-2H-thiocine, and
(5Z)-3,4,7,8-tetrahydro-2H-thiocine.
In some embodiments of a compound of Formula I or Formula Ia, at
least one Y is selected from the group consisting fluoro, chloro,
bromo, --CN, optionally substituted C.sub.1-C.sub.6 alkyl, --OH,
--OR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5, --C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.4C(.dbd.NR.sup.4)NR.sup.-
4R.sup.5, --NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.vHeteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl,
and --O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl. In certain
embodiments, at least one Y is selected from the group consisting
of fluoro, chloro, --CN, optionally substituted C.sub.1-C.sub.6
alkyl, --OH, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5) R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5, --NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.N
R.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4C(O)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR)NR.sup.4R.sup.5, --N(R.sup.4)
-Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vHeterocyclyl, and
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl. In further
embodiments, at least one Y is selected from the group consisting
of -Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5, and
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)-
NR.sup.4R.sup.5. In preferred embodiments, at least one Y is
selected from the group consisting of --NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
NR.sup.5C(.dbd.NR.sup.5)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--NR.sup.5C(O)CR.sup.6(NR.sup.4R.sup.5)(CR.sup.6R.sup.7).sub.vNR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5, --C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5.
In some embodiments, p is 0, 1, 2, or 3. In certain embodiments, p
is 1 or 2.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.4 and R.sup.5 are independently selected from the group
consisting of hydrogen, --OH, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted alkoxyalkyl,
optionally substituted hydroxyalkyl, and optionally substituted
heterocyclyl. In preferred embodiments, R.sup.4 and R.sup.5 are
independently hydrogen or optionally substituted C.sub.1-C.sub.6
alkyl.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen, optionally substituted C.sub.1-C.sub.6
alkyl, --OH, --NR.sup.4R.sup.5, and optionally substituted
heterocyclyl, or R.sup.6 and R.sup.7 taken together form an
optionally substituted heterocycle with the carbon to which they
are attached. In preferred embodiments, R.sup.6 and R.sup.7 are
independently hydrogen, fluoro, or optionally substituted
C.sub.1-C.sub.6 alkyl.
In certain embodiments of a compound of Formula I or Formula Ia,
the compound is selected from the group represented by the
following structures:
##STR00002## ##STR00003## ##STR00004## ##STR00005## ##STR00006##
##STR00007## ##STR00008## ##STR00009## ##STR00010## ##STR00011##
##STR00012## ##STR00013## ##STR00014## ##STR00015## or a
pharmaceutically acceptable salt, polymorph, solvate, prodrug,
N-oxide, or isomer thereof, wherein the compound is present in a
closed, cyclic form according to Formula I and as shown in the
structures above, in a open, acyclic form according to Formula Ia,
or mixtures thereof.
In some embodiments, the compound of Formula I or Formula Ia is the
stereoisomer represented by any of the structures shown herein. In
some embodiments, the compound of Formula I or Formula Ia is an
enantiomer of the stereoisomer represented by any of the structures
shown herein. In certain embodiments, the compound of Formula I or
Formula Ia is a diastereomer of the stereoisomer represented by any
of the structures shown herein. In some embodiments, the compound
of Formula I or Formula Ia is a mixture of enantiomers and/or
diastereomers of the stereoisomer represented by any of the
structures shown herein. In certain embodiments, the compound of
Formula I or Formula Ia is a racemate of the stereoisomer
represented by any of the structures herein.
In another aspect, provided herein are pharmaceutical compositions
comprising a compound Formula I or Formula Ia as described herein,
or a pharmaceutically acceptable salt, polymorph, solvate, prodrug,
N-oxide, or isomer thereof, and a pharmaceutically acceptable
excipient. In some embodiments, the pharmaceutical composition
further comprises a beta-lactam antibiotic. In certain embodiments,
the beta-lactam antibiotic is a penicillin, cephalosporin,
carbapenem, monobactam, bridged monobactam, or a combination
thereof.
In an additional aspect, provided herein are methods of treating a
bacterial infection in a subject, comprising administering to the
subject a compound of Formula I or Formula Ia as described herein
in combination with a therapeutically effective amount of beta
lactam antibiotic.
In a further aspect, provided herein are methods of treating a
bacterial infection in a subject, comprising administering to the
subject a pharmaceutical composition as described herein,
optionally in combination with a beta-lactam antibiotic. In certain
embodiments, the methods of treating a bacterial infection in a
subject comprise administering to the subject a pharmaceutical
composition as described herein in combination with a beta-lactam
antibiotic.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in
this specification are herein incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
Beta-lactamases are typically grouped into 4 classes: Ambler
classes A, B, C, and D, based on their amino acid sequences.
Enzymes in classes A, C, and D are active-site serine
beta-lactamases, while class B enzymes are Zn-dependent. Newer
generation cephalosporins and carbapenems were developed partly
based on their ability to evade the deactivating effect of the
early serine-based beta-lactamase variants. However, a recent surge
in new versions of serine-based beta-lactamases--for example Class
A Extended-Spectrum Beta-Lactamase (ESBL) enzymes, Class A
carbapenemases (e.g. KPC-2), chromosomal and plasmid mediated Class
C cephalosporinases (AmpC, CMY, etc.), and Class D
oxacillinases--as well as Class B metallo-beta-lactamases (e.g.
VIM, NDM) has begun to diminish the utility of the beta-lactam
antibiotic family, including the more recent generation beta-lactam
drugs, leading to a serious medical problem. Indeed the number of
catalogued serine-based beta-lactamases has exploded from less than
ten in the 1970s to over 750 variants (see, e.g., Jacoby &
Bush, "Amino Acid Sequences for TEM, SHV and OXA Extended-Spectrum
and Inhibitor Resistant .beta.-Lactamases", on the Lahey Clinic
website).
The commercially available beta-lactamase inhibitors (clavulanic
acid, sulbactam, tazobactam) were developed to address the
beta-lactamases that were clinically relevant in the 1970s and
1980s (e.g. penicillinases). These beta-lactamase inhibitors are
poorly active against the diversity of beta-lactamase enzymes (both
serine- and metallo-based) now emerging clinically. In addition,
these enzyme inhibitors are available only as fixed combinations
with penicillin derivatives. No combinations with cephalosporins
(or carbapenems) are clinically available. This fact, combined with
the increased use of newer generation cephalosporins and
carbapenems, is driving the selection and spread of the new
beta-lactamase variants (ESBLs, carbapenemases, chromosomal and
plasmid-mediated Class C, Class D oxacillinases, etc.). While
maintaining good inhibitory activity against ESBLs, the legacy
beta-lactamase inhibitors are largely ineffective against the new
Class A and Class B carbapenemases, against the chromosomal and
plasmid-mediated Class C cephalosporinases and against many of the
Class D oxacillinases.
To address this growing therapeutic vulnerability, and because
there are three major molecular classes of serine-based
beta-lactamases, and one major class of metallo-beta-lactamases,
and each of these classes contains significant numbers of
beta-lactamase variants, we have identified an approach for
developing novel beta-lactamase inhibitors with broad spectrum
functionality. In particular, we have identified an approach for
developing compounds that are active against both serine- and
metallo-based beta-lactamase enzymes. Compounds of the current
invention demonstrate potent activity across all four major classes
of beta-lactamases.
The present invention is directed to certain boron-based compounds
(boronic acids and cyclic boronic acid esters) which are
beta-lactamase inhibitors and antibacterial compounds. The
compounds and their pharmaceutically acceptable salts are useful
alone and in combination with beta-lactam antibiotics for the
treatment of bacterial infections, particularly antibiotic
resistant bacterial infections. Some embodiments include compounds,
compositions, pharmaceutical compositions, use and preparation
thereof.
Definitions
In the following description, certain specific details are set
forth in order to provide a thorough understanding of various
embodiments. However, one skilled in the art will understand that
the invention may be practiced without these details. In other
instances, well-known structures have not been shown or described
in detail to avoid unnecessarily obscuring descriptions of the
embodiments. Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is, as "including, but
not limited to." Further, headings provided herein are for
convenience only and do not interpret the scope or meaning of the
claimed invention.
Reference throughout this specification to "one embodiment" or "an
embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment. Thus, the appearances of the
phrases "in one embodiment" or "in an embodiment" in various places
throughout this specification are not necessarily all referring to
the same embodiment. Furthermore, the particular features,
structures, or characteristics may be combined in any suitable
manner in one or more embodiments. Also, as used in this
specification and the appended claims, the singular forms "a,"
"an," and "the" include plural referents unless the content clearly
dictates otherwise. It should also be noted that the term "or" is
generally employed in its sense including "and/or" unless the
content clearly dictates otherwise.
The term "antibiotic" refers to a compound or composition which
decreases the viability of a microorganism, or which inhibits the
growth or proliferation of a microorganism. The phrase "inhibits
the growth or proliferation" means increasing the generation time
(i.e., the time required for the bacterial cell to divide or for
the population to double) by at least about 2-fold. Preferred
antibiotics are those which can increase the generation time by at
least about 10-fold or more (e.g., at least about 100-fold or even
indefinitely, as in total cell death). As used in this disclosure,
an antibiotic is further intended to include an antimicrobial,
bacteriostatic, or bactericidal agent. Examples of antibiotics
suitable for use with respect to the present invention include
penicillins, cephalosporins and carbapenems.
The term ".beta.-lactam antibiotic" refers to a compound with
antibiotic properties that contains a .beta.-lactam functionality.
Non-limiting examples of .beta.-lactam antibiotics useful with
respect to the invention include penicillins, cephalosporins,
penems, carbapenems, and monobactams.
The term ".beta.-lactamase" denotes a protein capable of
inactivating a .beta.-lactam antibiotic. The .beta.-lactamase can
be an enzyme which catalyzes the hydrolysis of the .beta.-lactam
ring of a .beta.-lactam antibiotic. Of particular interest herein
are microbial .beta.-lactamases. The .beta.-lactamase may be, for
example, a serine .beta.-lactamase or a metallo-.beta.-lactamase.
.beta.-Lactamases of interest include those disclosed in an ongoing
website that monitors beta-lactamase nomenclature (www.lahey.org)
and in Bush, K. and G. A. Jacoby. 2010. An updated functional
classification of .beta.-lactamases. Antimicrob. Agents Chemother.
54:969-976. .beta.-Lactamases of particular interest herein include
.beta.-lactamases found in bacteria such as class A
.beta.-lactamases including the SHV, CTX-M and KPC subclasses,
class B .beta.-lactamases such as VIM, class C .beta.-lactamases
(both chromosomal and plasmid-mediated), and class D
.beta.-lactamases. The term ".beta.-lactamase inhibitor" refers to
a compound which is capable of inhibiting .beta.-lactamase
activity. Inhibiting .beta.-lactamase activity means inhibiting the
activity of a class A, B, C, or D .beta.-lactamase. For
antimicrobial applications inhibition at a 50% inhibitory
concentration is preferably achieved at or below about 100
micrograms/mL, or at or below about 50 micrograms/mL, or at or
below about 25 micrograms/mL. The terms "class A", "class B",
"class C", and "class D" .beta.-lactamases are understood by those
skilled in the art and are described in Bush, K. and G. A. Jacoby.
2010. An updated functional classification of .beta.-lactamases.
Antimicrob. Agents Chemother. 54:969-976.
The terms below, as used herein, have the following meanings,
unless indicated otherwise:
"Amino" refers to the --NH.sub.2 radical.
"Cyano" or "nitrile" refers to the --CN radical.
"Hydroxy" or "hydroxyl" refers to the --OH radical.
"Nitro" refers to the --NO.sub.2 radical.
"Oxo" refers to the .dbd.O substituent.
"Oxime" refers to the .dbd.N--OH substituent.
"Thioxo" refers to the .dbd.S substituent.
"Alkyl" refers to an optionally substituted straight-chain, or
optionally substituted branched-chain saturated hydrocarbon
monoradical having from one to about ten carbon atoms, more
preferably one to six carbon atoms, wherein an sp3-hybridized
carbon of the alkyl residue is attached to the rest of the molecule
by a single bond. Examples include, but are not limited to methyl,
ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,
2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,
2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,
4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,
4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,
2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups,
such as heptyl, octyl and the like. Whenever it appears herein, a
numerical range such as "C.sub.1-C.sub.6 alkyl" or "C.sub.1-6
alkyl", means that the alkyl group may consist of 1 carbon atom, 2
carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6
carbon atoms, although the present definition also covers the
occurrence of the term "alkyl" where no numerical range is
designated. Unless stated otherwise specifically in the
specification, an alkyl group may be optionally substituted as
described below, for example, with oxo, amino, nitrile, nitro,
hydroxyl, alkyl, alkylene, alkynyl, alkoxy, aryl, cycloalkyl,
heterocyclyl, heteroaryl, and the like.
"Alkenyl" refers to an optionally substituted straight-chain, or
optionally substituted branched-chain hydrocarbon monoradical
having one or more carbon-carbon double-bonds and having from two
to about ten carbon atoms, more preferably two to about six carbon
atoms, wherein an sp2-hybridized carbon of the alkenyl residue is
attached to the rest of the molecule by a single bond. The group
may be in either the cis or trans conformation about the double
bond(s), and should be understood to include both isomers. Examples
include, but are not limited to ethenyl (--CH.dbd.CH.sub.2),
1-propenyl (--CH.sub.2CH.dbd.CH.sub.2), isopropenyl
[--C(CH.sub.3).dbd.CH.sub.2], butenyl, 1,3-butadienyl and the like.
Whenever it appears herein, a numerical range such as
"C.sub.2-C.sub.6 alkenyl" or "C.sub.2-6 alkenyl", means that the
alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4
carbon atoms, 5 carbon atoms or 6 carbon atoms, although the
present definition also covers the occurrence of the term "alkenyl"
where no numerical range is designated.
"Alkynyl" refers to an optionally substituted straight-chain or
optionally substituted branched-chain hydrocarbon monoradical
having one or more carbon-carbon triple-bonds and having from two
to about ten carbon atoms, more preferably from two to about six
carbon atoms. Examples include, but are not limited to ethynyl,
2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it
appears herein, a numerical range such as "C.sub.2-C.sub.6 alkynyl"
or "C.sub.2-6 alkynyl", means that the alkynyl group may consist of
2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6
carbon atoms, although the present definition also covers the
occurrence of the term "alkynyl" where no numerical range is
designated.
"Alkylene" or "alkylene chain" refers to a straight or branched
divalent hydrocarbon chain. Unless stated otherwise specifically in
the specification, an alkylene group may be optionally substituted
as described below.
"Alkoxy" refers to a radical of the formula --OR.sub.a where
R.sub.a is an alkyl radical as defined. Unless stated otherwise
specifically in the specification, an alkoxy group may be
optionally substituted as described below.
"Aryl" refers to a radical derived from a hydrocarbon ring system
comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic
ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. Aryl radicals include, but are not limited to, aryl
radicals derived from the hydrocarbon ring systems of
aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene,
s-indacene, indane, indene, naphthalene, phenalene, phenanthrene,
pleiadene, pyrene, and triphenylene. Unless stated otherwise
specifically in the specification, the term "aryl" or the prefix
"ar-" (such as in "aralkyl") is meant to include aryl radicals that
are optionally substituted.
"Cycloalkyl" or "carbocycle" refers to a stable, non-aromatic,
monocyclic or polycyclic carbocyclic ring, which may include fused
or bridged ring systems, which is saturated or unsaturated.
Representative cycloalkyls or carbocycles include, but are not
limited to, cycloalkyls having from three to fifteen carbon atoms,
from three to ten carbon atoms, from three to eight carbon atoms,
from three to six carbon atoms, from three to five carbon atoms, or
three to four carbon atoms. Monocyclic cycloalkyls or carbocycles
include, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or
carbocycles include, for example, adamantyl, norbornyl, decalinyl,
bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin,
trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and
bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
Unless otherwise stated specifically in the specification, a
cycloalkyl or carbocycle group may be optionally substituted.
Illustrative examples of cycloalkyl groups include, but are not
limited to, the following moieties:
##STR00016## and the like.
"Fused" refers to any ring structure described herein which is
fused to an existing ring structure. When the fused ring is a
heterocyclyl ring or a heteroaryl ring, any carbon atom on the
existing ring structure which becomes part of the fused
heterocyclyl ring or the fused heteroaryl ring may be replaced with
a nitrogen atom.
"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
"Haloalkyl" refers to an alkyl radical, as defined above, that is
substituted by one or more halo radicals, as defined above, e.g.,
trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,
1,2-dibromoethyl, and the like. Unless stated otherwise
specifically in the specification, a haloalkyl group may be
optionally substituted.
"Haloalkoxy" similarly refers to a radical of the formula
--OR.sub.a where R.sub.a is a haloalkyl radical as defined. Unless
stated otherwise specifically in the specification, a haloalkoxy
group may be optionally substituted as described below.
"Heterocycloalkyl" or "heterocyclyl" or "heterocyclic ring" or
"heterocycle" refers to a stable 3- to 24-membered non-aromatic
ring radical comprising 2 to 23 carbon atoms and from one to 8
heteroatoms selected from the group consisting of nitrogen, oxygen,
phosphorous and sulfur. Unless stated otherwise specifically in the
specification, the heterocyclyl radical may be a monocyclic,
bicyclic, tricyclic or tetracyclic ring system, which may include
fused or bridged ring systems; and the nitrogen, carbon or sulfur
atoms in the heterocyclyl radical may be optionally oxidized; the
nitrogen atom may be optionally quaternized; and the heterocyclyl
radical may be partially or fully saturated. Examples of such
heterocyclyl radicals include, but are not limited to, azetidinyl,
dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,
imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl,
pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
12-crown-4, 15-crown-5, 18-crown-6, 21-crown-7, aza-18-crown-6,
diaza-18-crown-6, aza-21-crown-7, and diaza-21-crown-7. Unless
stated otherwise specifically in the specification, a heterocyclyl
group may be optionally substituted. Illustrative examples of
heterocycloalkyl groups, also referred to as non-aromatic
heterocycles, include:
##STR00017## and the like. The term heterocycloalkyl also includes
all ring forms of the carbohydrates, including but not limited to
the monosaccharides, the disaccharides and the oligosaccharides.
Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons
in the ring. It is understood that when referring to the number of
carbon atoms in a heterocycloalkyl, the number of carbon atoms in
the heterocycloalkyl is not the same as the total number of atoms
(including the heteroatoms) that make up the heterocycloalkyl (i.e.
skeletal atoms of the heterocycloalkyl ring). Unless stated
otherwise specifically in the specification, a heterocycloalkyl
group may be optionally substituted.
"Heteroaryl" refers to a 5- to 14-membered ring system radical
comprising hydrogen atoms, one to thirteen carbon atoms, one to six
heteroatoms selected from the group consisting of nitrogen, oxygen,
phosphorous and sulfur, and at least one aromatic ring. For
purposes of this invention, the heteroaryl radical may be a
monocyclic, bicyclic, tricyclic or tetracyclic ring system, which
may include fused or bridged ring systems; and the nitrogen, carbon
or sulfur atoms in the heteroaryl radical may be optionally
oxidized; the nitrogen atom may be optionally quaternized. Examples
include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,
benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,
benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
(benzothiophenyl), benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,
isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,
isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,
1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,
pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl,
isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).
Unless stated otherwise specifically in the specification, a
heteroaryl group may be optionally substituted.
All the above groups may be either substituted or unsubstituted.
The term "substituted" as used herein means any of the above groups
(e.g, alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl,
heterocyclyl and/or heteroaryl) may be further functionalized
wherein at least one hydrogen atom is replaced by a bond to a
non-hydrogen atom substituent. Unless stated specifically in the
specification, a substituted group may include one or more
substituents selected from: oxo, amino, --CO.sub.2H, nitrile,
nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl,
cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines,
alkylarylamines, diarylamines, trialkylammonium (--N+R.sub.3),
N-oxides, imides, and enamines; a silicon atom in groups such as
trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl
groups, triarylsilyl groups, perfluoroalkyl or perfluoroalkoxy, for
example, trifluoromethyl or trifluoromethoxy. "Substituted" also
means any of the above groups in which one or more hydrogen atoms
are replaced by a higher-order bond (e.g., a double- or
triple-bond) to a heteroatom such as oxygen in oxo, carbonyl,
carboxyl, and ester groups; and nitrogen in groups such as imines,
oximes, hydrazones, and nitriles. For example, "substituted"
includes any of the above groups in which one or more hydrogen
atoms are replaced with --NH.sub.2,
--NR.sub.gC(.dbd.O)NR.sub.gR.sub.h, --NR.sub.gC(.dbd.O)OR.sub.h,
--NR.sub.gSO.sub.2R.sub.h, --OC(.dbd.O)NR.sub.gR.sub.h, --OR.sub.g,
--SR.sub.g, --SOR.sub.g, --SO.sub.2R.sub.g, --OSO.sub.2R.sub.g,
--SO.sub.2OR.sub.g, .dbd.NSO.sub.2R.sub.g, and
--SO.sub.2NR.sub.gR.sub.h. In the foregoing, R.sub.g and R.sub.h
are the same or different and independently hydrogen, alkyl,
alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,
heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
In addition, each of the foregoing substituents may also be
optionally substituted with one or more of the above substituents.
Furthermore, any of the above groups may be substituted to include
one or more internal oxygen, sulfur, or nitrogen atoms. For
example, an alkyl group may be substituted with one or more
internal oxygen atoms to form an ether or polyether group.
Similarly, an alkyl group may be substituted with one or more
internal sulfur atoms to form a thioether, disulfide, etc.
The term "optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted alkyl" means either "alkyl" or "substituted alkyl" as
defined above. Further, an optionally substituted group may be
un-substituted (e.g., --CH.sub.2CH.sub.3), fully substituted (e.g.,
--CF.sub.2CF.sub.3), mono-substituted (e.g., --CH.sub.2CH.sub.2F)
or substituted at a level anywhere in-between fully substituted and
mono-substituted (e.g., --CH.sub.2CHF.sub.2, --CH.sub.2CF.sub.3,
--CF.sub.2CH.sub.3, --CFHCHF.sub.2, etc). It will be understood by
those skilled in the art with respect to any group containing one
or more substituents that such groups are not intended to introduce
any substitution or substitution patterns (e.g., substituted alkyl
includes optionally substituted cycloalkyl groups, which in turn
are defined as including optionally substituted alkyl groups,
potentially ad infinitum) that are sterically impractical and/or
synthetically non-feasible. Thus, any substituents described should
generally be understood as having a maximum molecular weight of
about 1,000 daltons, and more typically, up to about 500
daltons.
An "effective amount" or "therapeutically effective amount" refers
to an amount of a compound administered to a mammalian subject,
either as a single dose or as part of a series of doses, which is
effective to produce a desired therapeutic effect.
"Treatment" of an individual (e.g. a mammal, such as a human) or a
cell is any type of intervention used in an attempt to alter the
natural course of the individual or cell. In some embodiments,
treatment includes administration of a pharmaceutical composition,
subsequent to the initiation of a pathologic event or contact with
an etiologic agent and includes stabilization of the condition
(e.g., condition does not worsen) or alleviation of the condition.
In other embodiments, treatment also includes prophylactic
treatment (e.g., administration of a composition described herein
when an individual is suspected to be suffering from a bacterial
infection).
A "tautomer" refers to a proton shift from one atom of a molecule
to another atom of the same molecule. The compounds presented
herein may exist as tautomers. Tautomers are compounds that are
interconvertible by migration of a hydrogen atom, accompanied by a
switch of a single bond and adjacent double bond. In bonding
arrangements where tautomerization is possible, a chemical
equilibrium of the tautomers will exist. All tautomeric forms of
the compounds disclosed herein are contemplated. The exact ratio of
the tautomers depends on several factors, including temperature,
solvent, and pH. Some examples of tautomeric interconversions
include:
##STR00018##
A "metabolite" of a compound disclosed herein is a derivative of
that compound that is formed when the compound is metabolized. The
term "active metabolite" refers to a biologically active derivative
of a compound that is formed when the compound is metabolized. The
term "metabolized," as used herein, refers to the sum of the
processes (including, but not limited to, hydrolysis reactions and
reactions catalyzed by enzymes, such as, oxidation reactions) by
which a particular substance is changed by an organism. Thus,
enzymes may produce specific structural alterations to a compound.
For example, cytochrome P450 catalyzes a variety of oxidative and
reductive reactions while uridine diphosphate glucuronyl
transferases catalyze the transfer of an activated glucuronic-acid
molecule to aromatic alcohols, aliphatic alcohols, carboxylic
acids, amines and free sulfhydryl groups. Further information on
metabolism may be obtained from The Pharmacological Basis of
Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the
compounds disclosed herein can be identified either by
administration of compounds to a host and analysis of tissue
samples from the host, or by incubation of compounds with hepatic
cells in vitro and analysis of the resulting compounds. Both
methods are well known in the art. In some embodiments, metabolites
of a compound are formed by oxidative processes and correspond to
the corresponding hydroxy-containing compound. In some embodiments,
a compound is metabolized to pharmacologically active
metabolites.
Compounds
Described herein are compounds that modulate the activity of
beta-lactamase. In some embodiments, the compounds described herein
inhibit beta-lactamase. In certain embodiments, the compounds
described herein are useful in the treatment of bacterial
infections. In some embodiments, the bacterial infection is an
upper or lower respiratory tract infection, a urinary tract
infection, an intra-abdominal infection, or a skin infection.
In one aspect, provided herein are compounds of Formula I or
Formula Ia, or pharmaceutically acceptable salts, polymorphs,
solvates, tautomers, metabolites, or N-oxides thereof:
##STR00019## wherein: M is a bond, --O--, --S--, --S(O)--,
SO.sub.2--, or --N(R.sup.4)--; m is 0, 1, or 2; provided that when
HetA is attached to (CR.sup.1R.sup.2).sub.m through a ring nitrogen
atom, m=0 or 2. n is 0, 1, 2, or 3; provided that when n is 0, then
M is a bond; p is 0, 1, 2, or 3; X.sup.1 and X.sup.2 are
independently selected from --OH, --OR.sup.8, or F; Z is
>C.dbd.O, >C.dbd.S, or >SO.sub.2; HetA is an optionally
substituted non-aromatic heterocyclic ring system; each Y, provided
Y is not attached directly to a heteroatom of HetA, is selected
from the group consisting of: fluoro, chloro, bromo, --CN,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, optionally substituted
heterocycle, optionally substituted aryl, optionally substituted
heteroaryl, --OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)
(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--NR.sup.4(CR.sup.6R.sup.7).sub.vS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5) R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4-
R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.-
4R.sup.5,
--S(O).sub.0,1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.-
5C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -Heteroaryl-NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.v Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl,
--NR.sup.4R.sup.5R.sup.9+Q.sup.-,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.s-
ub.2, --(CR.sup.6R.sup.7).sub.v(T).sup.+Q.sup.-, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-; wherein:
T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; or two Ys
taken together with the carbon atoms to which they are attached
form an optionally substituted carbocycle, an optionally
substituted heterocycle, or a carbonyl group; in the case where Y
is attached directly to a heteroatom of HetA, Y is selected from
the group consisting of --(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.wNR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.su-
p.5, --NR.sup.4(CR.sup.6R.sup.7).sub.wOR.sup.10,
--(CR.sup.6R.sup.7).sub.wS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--S(O).sub.1,2NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.-
sup.5, --C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--S(O).sub.1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(-
.dbd.NR.sup.4)NR.sup.4R.sup.5, --C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --SO.sub.2R.sup.6,
--C(O)R.sup.6, --C(.dbd.O)OR.sup.6, --C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -aryl, -heteroaryl,
--C(O)N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
--Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--(CR.sup.6R.sup.7).sub.vO-Heterocyclyl, --R.sup.9+Q,
--(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5R.sup.9+ Q.sup.-,
--R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.sub.2
and --(CR.sup.6R.sup.7).sub.v(T).sup.+Q wherein: T is
pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; w is 2-4;
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --NR.sup.4R.sup.5, and --SR.sup.10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, fluoro, chloro, bromo, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, --OH, --OR.sub.10, --SR.sup.10, and --NR.sup.4R.sup.5,
or R.sup.1 and R.sup.2 taken together form an oxo, oxime, or an
optionally substituted carbocycle or optionally substituted
heterocycle with the carbon to which they are attached; R.sup.3 is
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or a
pharmaceutically acceptable prodrug; R.sup.d, R.sup.4 and R.sup.5
are independently selected from the group consisting of hydrogen,
--OH, --CN, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted aminoalkyl, optionally
substituted cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an
optionally substituted saccharide; or R.sup.4 and R.sup.5 taken
together form an optionally substituted heterocycle with the
nitrogen to which they are attached; R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
fluoro, chloro, bromo, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5,
--NR.sup.4SO.sub.2R.sup.5, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl;
or R.sup.6 and R.sup.7 taken together form an oxo, oxime, or an
optionally substituted carbocycle or an optionally substituted
heterocycle with the carbon to which they are attached; R.sup.8 is
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, or a pharmaceutically
acceptable boronate ester group; R.sup.9 is optionally substituted
C.sub.1-C.sub.6 alkyl; and R.sup.10 is optionally substituted
C.sub.1-C.sub.6 alkyl or optionally substituted C.sub.3-C.sub.6
cycloalkyl.
In some embodiments, provided herein are compounds of Formula I or
Formula Ia, or pharmaceutically acceptable salts, polymorphs,
solvates, tautomers, metabolites, or N-oxides thereof:
##STR00020## wherein: M is a bond, --O--, --S--, --S(O)--,
SO.sub.2--, or --N(R.sup.4)--; m is 0, 1, or 2; provided that when
HetA is attached to (CR.sup.1R.sup.2).sub.m through a ring nitrogen
atom, m=0 or 2. n is 0, 1, 2, or 3; provided that when n is 0, then
M is a bond; p is 1, 2, or 3; X.sup.1 and X.sup.2 are independently
selected from --OH, --OR.sup.8, or F; Z is >C.dbd.O,
>C.dbd.S, or >SO.sub.2; HetA is an optionally substituted
non-aromatic heterocyclic ring system; each Y, provided Y is not
attached directly to a heteroatom of HetA, is selected from the
group consisting of: fluoro, chloro, bromo, --CN, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocycle,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)
(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--NR.sup.4(CR.sup.6R.sup.7).sub.vS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5) R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4-
R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.-
4R.sup.5,
--S(O).sub.0,1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.-
5C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -Heteroaryl-NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.v Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl,
--NR.sup.4R.sup.5R.sup.9+Q.sup.-,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.s-
ub.2, --(CR.sup.6R.sup.7).sub.v(T).sup.+Q.sup.-, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-; wherein:
T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; or two Ys
taken together with the carbon atoms to which they are attached
form an optionally substituted carbocycle, an optionally
substituted heterocycle, or a carbonyl group; in the case where Y
is attached directly to a heteroatom of HetA, Y is selected from
the group consisting of --(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.wNR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.su-
p.5, --NR.sup.4(CR.sup.6R.sup.7).sub.wOR.sup.10,
--(CR.sup.6R.sup.7).sub.wS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--S(O).sub.1,2NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.-
sup.5, --C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--S(O).sub.1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(-
.dbd.NR.sup.4)NR.sup.4R.sup.5, --C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --SO.sub.2R.sup.6,
--C(.dbd.O)OR.sup.6, --C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -aryl, -heteroaryl,
--C(O)N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--(CR.sup.6R.sup.7).sub.v NR.sup.5-Heterocyclyl,
--(CR.sup.6R.sup.7).sub.vO-Heterocyclyl, --R.sup.9+Q.sup.-,
--(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.sub.2
and --(CR.sup.6R.sup.7).sub.v(T).sup.+Q wherein: T is
pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; w is 2-4;
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --NR.sup.4R.sup.5, and --SR.sup.10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, fluoro, chloro, bromo, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, --OH, --OR.sup.10, --SR.sup.10, and --NR.sup.4R.sup.5,
or R.sup.1 and R.sup.2 taken together form an oxo, oxime, or an
optionally substituted carbocycle or optionally substituted
heterocycle with the carbon to which they are attached; R.sup.3 is
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or a
pharmaceutically acceptable prodrug; R.sup.d, R.sup.4 and R.sup.5
are independently selected from the group consisting of hydrogen,
--OH, --CN, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted aminoalkyl, optionally
substituted cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an
optionally substituted saccharide; or R.sup.4 and R.sup.5 taken
together form an optionally substituted heterocycle with the
nitrogen to which they are attached; R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
fluoro, chloro, bromo, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5,
--NR.sup.4SO.sub.2R.sup.5, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl;
or R.sup.6 and R.sup.7 taken together form an oxo, oxime, or an
optionally substituted carbocycle or an optionally substituted
heterocycle with the carbon to which they are attached; R.sup.8 is
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, or a pharmaceutically
acceptable boronate ester group; R.sup.9 is optionally substituted
C.sub.1-C.sub.6 alkyl; and R.sup.10 is optionally substituted
C.sub.1-C.sub.6 alkyl or optionally substituted C.sub.3-C.sub.6
cycloalkyl.
In some embodiments, provided herein are compounds of Formula I or
Formula Ia, or pharmaceutically acceptable salts, polymorphs,
solvates, tautomers, metabolites, or N-oxides thereof:
##STR00021## wherein: M is a bond, --O--, --S--, --S(O)--,
SO.sub.2--, or --N(R.sup.4)--; m is 0, 1, or 2; provided that when
HetA is attached to (CR.sup.1R.sup.2).sub.m through a ring nitrogen
atom, m=0 or 2. n is 0, 1, 2, or 3; provided that when n is 0, then
M is a bond; p is 0, 1, 2, or 3; X.sup.1 and X.sup.2 are
independently selected from --OH, --OR.sup.8, or F; Z is
>C.dbd.O, >C.dbd.S, or >SO.sub.2; HetA is an optionally
substituted non-aromatic heterocyclic ring system, provided that
HetA is not 2-pyrrolidinyl or 4-piperidinyl; each Y, provided Y is
not attached directly to a heteroatom of HetA, is selected from the
group consisting of: fluoro, chloro, bromo, --CN, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocycle,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)
(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--NR.sup.4(CR.sup.6R.sup.7).sub.vS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5) R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.0,1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4-
R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5, --O(CR.sup.6R.sup.7).sub.v
C(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--S(O).sub.0,1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5, --NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -Heteroaryl-NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.v Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--O(CR.sup.6R.sup.7).sub.vNR.sup.5-Heterocyclyl,
--O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl,
--NR.sup.4R.sup.5R.sup.9+Q.sup.-,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--NR.sup.4R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.s-
ub.2, --(CR.sup.6R.sup.7).sub.v(T).sup.+Q.sup.-, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-;
wherein:
T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;
Q is a pharmaceutically acceptable counterion; and
v is 1-4; or two Ys taken together with the carbon atoms to which
they are attached form an optionally substituted carbocycle, an
optionally substituted heterocycle, or a carbonyl group; in the
case where Y is attached directly to a heteroatom of HetA, Y is
selected from the group consisting of
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(O)(CR.sup.6R.sup.7)).sub.vNR.sup.4R.-
sup.5,
--(CR.sup.6R.sup.7).sub.wNR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.s-
up.5, --NR.sup.4(CR.sup.6R.sup.7).sub.wOR.sup.10,
--(CR.sup.6R.sup.7).sub.wS(O).sub.0,1,2R.sup.10,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--S(O).sub.1,2NR.sup.4(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5,
--C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.wN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--S(O).sub.1,2(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.-
sup.5, --C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--S(O).sub.1,2--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(-
.dbd.NR.sup.4)NR.sup.4R.sup.5, --C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --SO.sub.2R.sup.6,
--C(.dbd.O)OR.sup.6, --C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
--SO.sub.2NR.sup.4R.sup.5, -aryl, -heteroaryl,
--C(O)N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--(CR.sup.6R.sup.7).sub.vNR.sup.5-Heteroaryl,
--(CR.sup.6R.sup.7).sub.v NR.sup.5-Heterocyclyl,
--(CR.sup.6R.sup.7).sub.vO-Heterocyclyl, --R.sup.9+Q.sup.-,
--(CR.sup.6R.sup.7).sub.wNR.sup.4R.sup.5R.sup.9+Q.sup.-,
--R.sup.9+(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5R.sup.9+Q.sup.-.sub.2
and --(CR.sup.6R.sup.7).sub.v(T).sup.+Q wherein: T is
pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a
pharmaceutically acceptable counterion; and v is 1-4; w is 2-4;
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OH, --OR.sup.10, --NR.sup.4R.sup.5, and --SR.sup.10; R.sup.1 and
R.sup.2 are independently selected from the group consisting of
hydrogen, fluoro, chloro, bromo, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.3-C.sub.6
cycloalkyl, --OH, --OR.sup.10, --SR.sup.10, and --NR.sup.4R.sup.5,
or R.sup.1 and R.sup.2 taken together form an oxo, oxime, or an
optionally substituted carbocycle or optionally substituted
heterocycle with the carbon to which they are attached; R.sup.3 is
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, or a
pharmaceutically acceptable prodrug; R.sup.d, R.sup.4 and R.sup.5
are independently selected from the group consisting of hydrogen,
--OH, --CN, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted aminoalkyl, optionally
substituted cycloalkyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted cycloalkylalkyl, optionally substituted
heterocyclylalkyl, optionally substituted aralkyl, optionally
substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an
optionally substituted saccharide; or R.sup.4 and R.sup.5 taken
together form an optionally substituted heterocycle with the
nitrogen to which they are attached; R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
fluoro, chloro, bromo, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkoxyalkyl, optionally substituted
hydroxyalkyl, optionally substituted C.sub.3-C.sub.6 cycloalkyl,
--OH, --OR.sup.10, --SR.sup.10, --NR.sup.4R.sup.5,
--NR.sup.4C(O)R.sup.5, --C(O)NR.sup.4R.sup.5,
--NR.sup.4SO.sub.2R.sup.5, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl;
or R.sup.6 and R.sup.7 taken together form an oxo, oxime, or an
optionally substituted carbocycle or an optionally substituted
heterocycle with the carbon to which they are attached; R.sup.8 is
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.3-C.sub.6 cycloalkyl, or a pharmaceutically
acceptable boronate ester group; R.sup.9 is optionally substituted
C.sub.1-C.sub.6 alkyl; and R.sup.10 is optionally substituted
C.sub.1-C.sub.6 alkyl or optionally substituted C.sub.3-C.sub.6
cycloalkyl.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.a, R.sup.b, and R.sup.c are independently selected from the
group consisting of hydrogen, fluoro, chloro, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.3-C.sub.6 cycloalkyl, --OH, --OR.sup.10, --NR.sup.4R.sup.5,
and --SR.sup.10. In certain embodiments, R.sup.a, R.sup.b, and
R.sup.c are independently hydrogen, fluoro, or chloro. In preferred
embodiments, R.sup.a, R.sup.b, and R.sup.c are hydrogen.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.3 is hydrogen, methyl, ethyl, propyl, butyl, or isopropyl. In
preferred embodiments, R.sup.3 is hydrogen.
In some embodiments of a compound of Formula I or Formula Ia,
X.sup.1 and X.sup.2 are --OH.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.d is hydrogen or C.sub.1-C.sub.4-alkyl. In preferred
embodiments, R.sup.d is hydrogen.
In some embodiments of a compound of Formula I or Formula Ia, Z is
Z is >C.dbd.O or >SO.sub.2. In preferred embodiments, Z is
>C.dbd.O.
In some embodiments of a compound of Formula I or Formula Ia, HetA
is selected from the group consisting of azetidine, oxetane
thietane, pyrrolidine, oxazolidine, isoxazolidine, thiazolidine,
isothiazolidine, imidazolidine, pyrazolidine,
2,5-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyrrole, 4,5-dihydrooxazole,
4,5-dihydroisoxazole, 4,5-dihydrothiazole, 4,5-dihydroisothiazole,
4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-imidazole,
2,5-dihydro-1H-pyrrole, piperidine, morpholine, thiomorpholine,
tetrahydrothiopyran, tetrahydropyran, 1,4-oxathiane, piperazine,
hexahydropyrimidine, hexahydropyridazine,
1,4,5,6-tetrahydropyrimidine, 1,3-oxazinane,
5,6-dihydro-4H-1,3-oxazine, 1,3-thiazinane,
5,6-dihydro-4H-1,3-thiazine, 1,4,5,6-tetrahydropyridazine,
1,2,3,6-tetrahydropyrazine, 1,2,3,6-tetrahydropyridine,
1,2,3,6-tetrahydropyridazine, azepane, 1,3-oxazepane,
1,4-oxazepane, 1,3-diazepane, 1,4-diazepane, 1,3-thiazepane,
1,4-thiazepane, diazepane, oxazepane, thiazepane,
3,4,5,6-tetrahydro-2H-azepine, 4,5,6,7-tetrahydro-1H-1,3-diazepine,
4,5,6,7-tetrahydro-1,3-oxazepine,
4,5,6,7-tetrahydro-1,3-thiazepine,
2,3,4,7-tetrahydro-1H-1,3-diazepine, and
2,3,4,7-tetrahydro-1,3-oxazepine.
In some embodiments of a compound of Formula I or Formula Ia, at
least one Y is selected from the group consisting fluoro, chloro,
--CN, optionally substituted C.sub.1-C.sub.6 alkyl, --OH,
--OR.sup.10, --NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5, --C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--S(O).sub.0,1,2NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--OC(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--O (CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--O(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.-
4R.sup.5, --NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4SO.sub.2R.sup.6,
--NR.sup.4C(O)R.sup.6, --NR.sup.4C(.dbd.O)OR.sup.6,
--C(O)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
-Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.s-
up.4R.sup.5, --(CR.sup.6R.sup.7).sub.vHeteroaryl,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl, --O-Heteroaryl,
--O-Heterocyclyl, --NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl,
--O(CR.sup.6R.sup.7).sub.vHeteroaryl,
--O(CR.sup.6R.sup.7).sub.vHeterocyclyl, and
--O(CR.sup.6R.sup.7).sub.vO-Heterocyclyl. In certain embodiments,
at least one Y is selected from the group consisting fluoro,
chloro, --CN, optionally substituted C.sub.1-C.sub.6 alkyl, --OH,
--NR.sup.4R.sup.5, --(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(O)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.5C(.dbd.NR.sup.7)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.NR.sup.4)NR.sup.4-
R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.4)NR.sup.5C(.dbd.N-
R.sup.4)NR.sup.4R.sup.5, --NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6, --NR.sup.4C(O) R.sup.6,
--(CR.sup.6R.sup.7).sub.vC(O)NR.sup.4R.sup.5,
-Heterocyclyl-NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vHeterocyclyl, and
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeterocyclyl. In further
embodiments, at least one Y is selected from the group
consisting
of -Heteroaryl-NR.sup.4R.sup.5, -Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--N(R.sup.4)--Heteroaryl-NR.sup.4R.sup.5,
--N(R.sup.4)--Heterocyclyl-NR.sup.4R.sup.5,
-Heteroaryl-C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
-Heterocyclyl-C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vHeteroaryl-N(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.s-
up.5, and
--(CR.sup.6R.sup.7).sub.vHeterocyclyl-N(R.sup.4)C(.dbd.NR.sup.5)-
NR.sup.4R.sup.5. In specific embodiments, at least one Y is
2-(NR.sub.4R.sub.5)-pyridyl, 2-(NR.sub.4R.sub.5)-pyrimidinyl,
2-(NR.sub.4R.sub.5)-thiazolyl, 2-(NR.sub.4R.sub.5)-imidazolyl,
3-(NR.sub.4R.sub.5)-pyrazolyl, 3-(R.sub.4R.sub.5N)-isothiazolyl,
2-(R.sub.4R.sub.5N)-oxazolyl, piperidine, pyrrolidine,
4-amino-piperidinyl, 3-amino-pyrrolidinyl, piperazine, or
4-carboximidoyl-piperazinyl. In preferred embodiments, at least one
Y is selected from the group consisting of --NR.sup.4R.sup.5,
--NR.sup.4C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--C(.dbd.NR.sup.4)NR.sup.4R.sup.5,
--N(R.sup.4)C(.dbd.NR.sup.5)R.sup.6,
--(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vOR.sup.10,
--(CR.sup.6R.sup.7).sub.vNR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
NR.sup.5C(.dbd.NR.sup.5)NR.sup.4(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5,
--NR.sup.4(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(.dbd.NR.sup.5)NR.sup.4R.sup.-
5,
--NR.sup.5C(O)CR.sup.6(NR.sup.4R.sup.5)(CR.sup.6R.sup.7).sub.vNR.sup.4R-
.sup.5, --(CR.sup.6R.sup.7).sub.vC(.dbd.NR.sup.5)NR.sup.4R.sup.5,
--(CR.sup.6R.sup.7).sub.vN(R.sup.4)C(O)(CR.sup.6R.sup.7).sub.vNR.sup.4R.s-
up.5, --C(.dbd.NR.sup.4)NR.sup.4C(O)R.sup.6,
--NR.sup.4(CR.sup.6R.sup.7).sub.vHeteroaryl, and
--O(CR.sup.6R.sup.7).sub.vNR.sup.4R.sup.5.
In some embodiments, p is 0, 1, 2, or 3. In certain embodiments, p
is 1 or 2. In some embodiments, p is 2. In other embodiments, p is
1.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.4 and R.sup.5 are independently selected from the group
consisting of hydrogen, --OH, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted alkoxyalkyl,
optionally substituted hydroxyalkyl, and optionally substituted
heterocyclyl. In preferred embodiments, R.sup.4 and R.sup.5 are
independently hydrogen or optionally substituted C.sub.1-C.sub.6
alkyl.
In some embodiments of a compound of Formula I or Formula Ia,
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen, optionally substituted C.sub.1-C.sub.6
alkyl, --OH, --NR.sup.4R.sup.5, and optionally substituted
heterocyclyl, or R.sup.6 and R.sup.7 taken together form an
optionally substituted heterocycle with the carbon to which they
are attached. In preferred embodiments, R.sup.6 and R.sup.7 are
independently hydrogen, fluoro, or optionally substituted
C.sub.1-C.sub.6 alkyl.
Preparation of Compounds
Described herein are compounds of Formula I or Formula Ia that
inhibit the activity of beta-lactamases, and processes for their
preparation. Also described herein are pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, pharmaceutically
active metabolites, and pharmaceutically acceptable prodrugs of
such compounds. Pharmaceutical compositions comprising at least one
such compound or a pharmaceutically acceptable salt,
pharmaceutically acceptable solvate, pharmaceutically active
metabolite or pharmaceutically acceptable prodrug of such compound,
and a pharmaceutically acceptable excipient are also provided.
Compounds of Formula I or Formula Ia may be synthesized using
standard synthetic reactions known to those of skill in the art or
using methods known in the art. The reactions can be employed in a
linear sequence to provide the compounds or they may be used to
synthesize fragments which are subsequently joined by the methods
known in the art.
The starting material used for the synthesis of the compounds
described herein may be synthesized or can be obtained from
commercial sources, such as, but not limited to, Aldrich Chemical
Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma Chemical
Co. (St. Louis, Mo.). The compounds described herein, and other
related compounds having different substituents can be synthesized
using techniques and materials known to those of skill in the art,
such as described, for example, in March, ADVANCED ORGANIC
CHEMISTRY 4.sup.th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED
ORGANIC CHEMISTRY 4.sup.th Ed., Vols. A and B (Plenum 2000, 2001);
Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3.sup.rd
Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic
Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's
Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals
(Elsevier Science Publishers, 1989); Organic Reactions, Volumes
1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive
Organic Transformations (VCH Publishers Inc., 1989). (all of which
are incorporated by reference in their entirety). Other methods for
the synthesis of compounds described herein may be found in
International Patent Publication No. WO 01/01982901, Arnold et al.
Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170;
Burchat et al. Bioorganic & Medicinal Chemistry Letters 12
(2002) 1687-1690. General methods for the preparation of compounds
as disclosed herein may be derived from known reactions in the
field, and the reactions may be modified by the use of appropriate
reagents and conditions, as would be recognized by the skilled
person, for the introduction of the various moieties found in the
formulas as provided herein.
The products of the reactions may be isolated and purified, if
desired, using conventional techniques, including, but not limited
to, filtration, distillation, crystallization, chromatography and
the like. Such materials may be characterized using conventional
means, including physical constants and spectral data.
Compounds described herein may be prepared as a single isomer or a
mixture of isomers.
Further Forms of Compounds Disclosed Herein
Isomers
In some embodiments, due to the oxophilic nature of the boron atom,
the compounds described herein may convert to or exist in
equilibrium with alternate forms, particularly in milieu that
contain water (aqueous solution, plasma, etc.). Accordingly, the
compounds described herein may exist in an equilibrium between the
"closed" cyclic form shown in Formula I and the "open" acyclic form
shown in Figure Ia. In addition, the compounds described herein may
associate into intramolecular dimers, trimers, and related
combinations.
Furthermore, in some embodiments, the compounds described herein
exist as geometric isomers. In some embodiments, the compounds
described herein possess one or more double bonds. The compounds
presented herein include all cis, trans, syn, anti, entgegen (E),
and zusammen (Z) isomers as well as the corresponding mixtures
thereof. In some situations, compounds exist as tautomers. The
compounds described herein include all possible tautomers within
the formulas described herein. In some situations, the compounds
described herein possess one or more chiral centers and each center
exists in the R configuration, or S configuration. The compounds
described herein include all diastereomeric, enantiomeric, and
epimeric forms as well as the corresponding mixtures thereof. In
additional embodiments of the compounds and methods provided
herein, mixtures of enantiomers and/or diastereoisomers, resulting
from a single preparative step, combination, or interconversion are
useful for the applications described herein. In some embodiments,
the compounds described herein are prepared as their individual
stereoisomers by reacting a racemic mixture of the compound with an
optically active resolving agent to form a pair of
diastereoisomeric compounds, separating the diastereomers and
recovering the optically pure enantiomers. In some embodiments,
dissociable complexes are preferred (e.g., crystalline
diastereomeric salts). In some embodiments, the diastereomers have
distinct physical properties (e.g., melting points, boiling points,
solubilities, reactivity, etc.) and are separated by taking
advantage of these dissimilarities. In some embodiments, the
diastereomers are separated by chiral chromatography, or
preferably, by separation/resolution techniques based upon
differences in solubility. In some embodiments, the optically pure
enantiomer is then recovered, along with the resolving agent, by
any practical means that would not result in racemization.
Labeled Compounds
In some embodiments, the compounds described herein exist in their
isotopically-labeled forms. In some embodiments, the methods
disclosed herein include methods of treating diseases by
administering such isotopically-labeled compounds. In some
embodiments, the methods disclosed herein include methods of
treating diseases by administering such isotopically-labeled
compounds as pharmaceutical compositions. Thus, in some
embodiments, the compounds disclosed herein include
isotopically-labeled compounds, which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, sulfur, fluorine and chloride, such as .sup.2H,
.sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl,
respectively. Compounds described herein, and the metabolites,
pharmaceutically acceptable salts, esters, prodrugs, solvate,
hydrates or derivatives thereof which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labeled compounds, for
example those into which radioactive isotopes such as .sup.3H and
.sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i. e., .sup.3H and
carbon-14, i. e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavy isotopes such as deuterium, i.e., .sup.2H, produces
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements. In some embodiments, the isotopically labeled
compounds, pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative thereof is prepared by any suitable
method.
In some embodiments, the compounds described herein are labeled by
other means, including, but not limited to, the use of chromophores
or fluorescent moieties, bioluminescent labels, or chemiluminescent
labels.
Pharmaceutically Acceptable Salts
In some embodiments, the compounds described herein exist as their
pharmaceutically acceptable salts. In some embodiments, the methods
disclosed herein include methods of treating diseases by
administering such pharmaceutically acceptable salts. In some
embodiments, the methods disclosed herein include methods of
treating diseases by administering such pharmaceutically acceptable
salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic
or basic groups and therefore react with any of a number of
inorganic or organic bases, and inorganic and organic acids, to
form a pharmaceutically acceptable salt. In some embodiments, these
salts are prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound in its free form with a suitable acid
or base, and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those salts
prepared by reaction of the compounds described herein with a
mineral, organic acid or inorganic base, such salts including,
acetate, acrylate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, bisulfite, bromide, butyrate,
butyn-1,4-dioate, camphorate, camphorsulfonate, caproate,
caprylate, chlorobenzoate, chloride, citrate,
cyclopentanepropionate, decanoate, digluconate,
dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
hexyne-1,6-dioate, hydroxybenzoate, .gamma.-hydroxybutyrate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate,
mandelate metaphosphate, methanesulfonate, methoxybenzoate,
methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate,
2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,
phenylacetate, phenylbutyrate, propanesulfonate, salicylate,
succinate, sulfate, sulfite, succinate, suberate, sebacate,
sulfonate, tartrate, thiocyanate, tosylate undeconate and
xylenesulfonate.
Further, the compounds described herein can be prepared as
pharmaceutically acceptable salts formed by reacting the free base
form of the compound with a pharmaceutically acceptable inorganic
or organic acid, including, but not limited to, inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid metaphosphoric acid, and the like; and
organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic
acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric
acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid,
citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic
acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid,
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric acid, gluconic acid, glutamic acid,
hydroxynaphthoic acid, salicylic acid, stearic acid and muconic
acid. In some embodiments, other acids, such as oxalic, while not
in themselves pharmaceutically acceptable, are employed in the
preparation of salts useful as intermediates in obtaining the
compounds of the invention and their pharmaceutically acceptable
acid addition salts.
In some embodiments, those compounds described herein which
comprise a free acid group react with a suitable base, such as the
hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically
acceptable metal cation, with ammonia, or with a pharmaceutically
acceptable organic primary, secondary, tertiary, or quaternary
amine. Representative salts include the alkali or alkaline earth
salts, like lithium, sodium, potassium, calcium, and magnesium, and
aluminum salts and the like. Illustrative examples of bases include
sodium hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate, N.sup.+(C.sub.1-4 alkyl).sub.4, and the like.
Representative organic amines useful for the formation of base
addition salts include ethylamine, diethylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine and the like. It should be
understood that the compounds described herein also include the
quaternization of any basic nitrogen-containing groups they
contain. It should be understood that the compounds described
herein also include the quaternization of any boron-containing
groups they contain. Such a quarternization could result from the
treatment of the Lewis acidic boron with a Lewis base to form a
complex or salt. In some embodiments, water or oil-soluble or
dispersible products are obtained by such quaternization.
Solvates
In some embodiments, the compounds described herein exist as
solvates. The invention provides for methods of treating diseases
by administering such solvates. The invention further provides for
methods of treating diseases by administering such solvates as
pharmaceutical compositions.
Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and, in some embodiments, are formed during
the process of crystallization with pharmaceutically acceptable
solvents such as water, ethanol, and the like. Hydrates are formed
when the solvent is water, or alcoholates are formed when the
solvent is alcohol. Solvates of the compounds described herein can
be conveniently prepared or formed during the processes described
herein. By way of example only, hydrates of the compounds described
herein can be conveniently prepared by recrystallization from an
aqueous/organic solvent mixture, using organic solvents including,
but not limited to, dioxane, tetrahydrofuran or methanol. In
addition, the compounds provided herein can exist in unsolvated as
well as solvated forms. In general, the solvated forms are
considered equivalent to the unsolvated forms for the purposes of
the compounds and methods provided herein.
Polymorphs
In some embodiments, the compounds described herein exist as
polymorphs. The invention provides for methods of treating diseases
by administering such polymorphs. The invention further provides
for methods of treating diseases by administering such polymorphs
as pharmaceutical compositions.
Thus, the compounds described herein include all their crystalline
forms, known as polymorphs. Polymorphs include the different
crystal packing arrangements of the same elemental composition of a
compound. In certain instances, polymorphs have different X-ray
diffraction patterns, infrared spectra, melting points, density,
hardness, crystal shape, optical and electrical properties,
stability, and solubility. In certain instances, various factors
such as the recrystallization solvent, rate of crystallization, and
storage temperature cause a single crystal form to dominate.
Prodrugs
In some embodiments, the compounds described herein exist in
prodrug form. The invention provides for methods of treating
diseases by administering such prodrugs. The invention further
provides for methods of treating diseases by administering such
prodrugs as pharmaceutical compositions.
Prodrugs are generally drug precursors that, following
administration to an individual and subsequent absorption, are
converted to an active, or a more active species via some process,
such as conversion by a metabolic pathway. Some prodrugs have a
chemical group present on the prodrug that renders it less active
and/or confers solubility or some other property to the drug. Once
the chemical group has been cleaved and/or modified from the
prodrug the active drug is generated. Prodrugs are often useful
because, in some situations, they are easier to administer than the
parent drug. They are, for instance, bioavailable by oral
administration whereas the parent is not. In certain instances, the
prodrug also has improved solubility in pharmaceutical compositions
over the parent drug. An example, without limitation, of a prodrug
would be a compound as described herein which is administered as an
ester (the "prodrug") to facilitate transmittal across a cell
membrane where water solubility is detrimental to mobility but
which then is metabolically hydrolyzed to the carboxylic acid, the
active entity, once inside the cell where water-solubility is
beneficial. A further example of a prodrug might be a short peptide
(polyamino acid) bonded to an acid group where the peptide is
metabolized to reveal the active moiety. (See for example
Bundgaard, "Design and Application of Prodrugs" in A Textbook of
Drug Design and Development, Krosgaard-Larsen and Bundgaard, Ed.,
1991, Chapter 5, 113-191, which is incorporated herein by
reference).
In some embodiments, prodrugs are designed as reversible drug
derivatives, for use as modifiers to enhance drug transport to
site-specific tissues. The design of prodrugs to date has been to
increase the effective water solubility of the therapeutic compound
for targeting to regions where water is the principal solvent.
Additionally, prodrug derivatives of compounds described herein can
be prepared by methods described herein are otherwise known in the
art (for further details see Saulnier et al., Bioorganic and
Medicinal Chemistry Letters, 1994, 4, 1985). By way of example
only, appropriate prodrugs can be prepared by reacting a
non-derivatized compound with a suitable carbamylating agent, such
as, but not limited to, 1,1-acyloxyalkylcarbanochloridate,
para-nitrophenyl carbonate, or the like. Prodrug forms of the
herein described compounds, wherein the prodrug is metabolized in
vivo to produce a derivative as set forth herein are included
within the scope of the claims. Indeed, some of the
herein-described compounds are prodrugs for another derivative or
active compound.
In some embodiments, prodrugs include compounds wherein an amino
acid residue, or a polypeptide chain of two or more (e. g., two,
three or four) amino acid residues is covalently joined through an
amide or ester bond to a free amino, hydroxy or carboxylic acid
group of compounds of the present invention. The amino acid
residues include but are not limited to the 20 naturally occurring
amino acids and also includes 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine,
gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,
ornithine and methionine sulfone. In other embodiments, prodrugs
include compounds wherein a nucleic acid residue, or an
oligonucleotide of two or more (e. g., two, three or four) nucleic
acid residues is covalently joined to a compound of the present
invention.
Pharmaceutically acceptable prodrugs of the compounds described
herein also include, but are not limited to, esters, carbonates,
thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,
quaternary derivatives of tertiary amines, N-Mannich bases, Schiff
bases, amino acid conjugates, phosphate esters, metal salts and
sulfonate esters. Compounds having free amino, amido, hydroxy or
carboxylic groups can be converted into prodrugs. For instance,
free carboxyl groups can be derivatized as amides or alkyl esters.
In certain instances, all of these prodrug moieties incorporate
groups including but not limited to ether, amine and carboxylic
acid functionalities.
Hydroxy prodrugs include esters, such as though not limited to,
acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,
alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate
esters, sulfonate esters, sulfate esters and disulfide containing
esters; ethers, amides, carbamates, hemisuccinates,
dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews 1996, 19, 115.
Amine derived prodrugs include, but are not limited to the
following groups and combinations of groups:
##STR00022## as well as sulfonamides and phosphonamides.
In certain instances, sites on any aromatic ring portions are
susceptible to various metabolic reactions, therefore incorporation
of appropriate substituents on the aromatic ring structures, can
reduce, minimize or eliminate this metabolic pathway.
Metabolites
In some embodiments, compounds of Formula I or Formula Ia are
susceptible to various metabolic reactions. Therefore, in some
embodiments, incorporation of appropriate substituents into the
structure will reduce, minimize, or eliminate a metabolic pathway.
In specific embodiments, the appropriate substituent to decrease or
eliminate the susceptibility of an aromatic ring to metabolic
reactions is, by way of example only, a halogen, or an alkyl
group.
In additional or further embodiments, the compounds of Formula I or
Formula Ia described herein are metabolized upon administration to
an organism in need to produce a metabolite that is then used to
produce a desired effect, including a desired therapeutic
effect.
Pharmaceutical Compositions/Formulations
In another aspect, provided herein are pharmaceutical compositions
comprising a compound of Formula I or Formula Ia as described
herein, or a pharmaceutically acceptable salt, polymorph, solvate,
prodrug, N-oxide, or isomer thereof, and a pharmaceutically
acceptable excipient. In some embodiments, the pharmaceutical
composition further comprises a beta-lactam antibiotic. In certain
embodiments, the beta-lactam antibiotic is a penicillin,
cephalosporin, carbapenem, monobactam, bridged monobactam, or a
combination thereof.
In some embodiments, the compounds described herein are formulated
into pharmaceutical compositions. Pharmaceutical compositions are
formulated in a conventional manner using one or more
pharmaceutically acceptable inactive ingredients that facilitate
processing of the active compounds into preparations that can be
used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen. A summary of pharmaceutical
compositions described herein can be found, for example, in
Remington: The Science and Practice of Pharmacy, Nineteenth Ed
(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical
Dosage Forms, Marcel Decker, New York, N.Y., 1980; and
Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
(Lippincott Williams & Wilkins 1999), herein incorporated by
reference for such disclosure.
Provided herein are pharmaceutical compositions that include a
compound of Formula I or Formula Ia and at least one
pharmaceutically acceptable inactive ingredient. In some
embodiments, the compounds described herein are administered as
pharmaceutical compositions in which a compound of Formula I or
Formula Ia is mixed with other active ingredients, as in
combination therapy. In other embodiments, the pharmaceutical
compositions include other medicinal or pharmaceutical agents,
carriers, adjuvants, preserving, stabilizing, wetting or
emulsifying agents, solution promoters, salts for regulating the
osmotic pressure, and/or buffers. In yet other embodiments, the
pharmaceutical compositions include other therapeutically valuable
substances.
A pharmaceutical composition, as used herein, refers to a mixture
of a compound of Formula I or Formula Ia with other chemical
components (i.e. pharmaceutically acceptable inactive ingredients),
such as carriers, excipients, binders, filling agents, suspending
agents, flavoring agents, sweetening agents, disintegrating agents,
dispersing agents, surfactants, lubricants, colorants, diluents,
solubilizers, moistening agents, plasticizers, stabilizers,
penetration enhancers, wetting agents, anti-foaming agents,
antioxidants, preservatives, or one or more combinations thereof.
The pharmaceutical composition facilitates administration of the
compound to an organism. In practicing the methods of treatment or
use provided herein, therapeutically effective amounts of compounds
described herein are administered in a pharmaceutical composition
to a mammal having a disease, disorder, or condition to be treated.
In some embodiments, the mammal is a human. A therapeutically
effective amount can vary widely depending on the severity of the
disease, the age and relative health of the subject, the potency of
the compound used and other factors. The compounds can be used
singly or in combination with one or more therapeutic agents as
components of mixtures.
The pharmaceutical formulations described herein are administered
to a subject by appropriate administration routes, including but
not limited to, oral, parenteral (e.g., intravenous, subcutaneous,
intramuscular), intranasal, buccal, topical, rectal, or transdermal
administration routes. The pharmaceutical formulations described
herein include, but are not limited to, aqueous liquid dispersions,
liquids, gels, syrups, elixirs, slurries, suspensions,
self-emulsifying dispersions, solid solutions, liposomal
dispersions, aerosols, solid oral dosage forms, powders, immediate
release formulations, controlled release formulations, fast melt
formulations, tablets, capsules, pills, powders, dragees,
effervescent formulations, lyophilized formulations, delayed
release formulations, extended release formulations, pulsatile
release formulations, multiparticulate formulations, and mixed
immediate and controlled release formulations.
Pharmaceutical compositions including a compound of Formula I or
Formula Ia are manufactured in a conventional manner, such as, by
way of example only, by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or compression processes.
The pharmaceutical compositions will include at least one compound
of Formula I or Formula Ia as an active ingredient in free-acid or
free-base form, or in a pharmaceutically acceptable salt form. In
addition, the methods and pharmaceutical compositions described
herein include the use of N-oxides (if appropriate), crystalline
forms, amorphous phases, as well as active metabolites of these
compounds having the same type of activity. In some embodiments,
compounds described herein exist in unsolvated form or in solvated
forms with pharmaceutically acceptable solvents such as water,
ethanol, and the like. The solvated forms of the compounds
presented herein are also considered to be disclosed herein.
Pharmaceutical preparations for oral use are obtained by mixing one
or more solid excipient with one or more of the compounds described
herein, optionally grinding the resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain tablets or dragee cores. Suitable excipients
include, for example, fillers such as sugars, including lactose,
sucrose, mannitol, or sorbitol; cellulose preparations such as, for
example, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methylcellulose, microcrystalline
cellulose, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose; or others such as: polyvinylpyrrolidone
(PVP or povidone) or calcium phosphate. If desired, disintegrating
agents are added, such as the cross-linked croscarmellose sodium,
polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such
as sodium alginate. In some embodiments, dyestuffs or pigments are
added to the tablets or dragee coatings for identification or to
characterize different combinations of active compound doses.
Pharmaceutical preparations that are administered orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules contain the active ingredients in admixture
with filler such as lactose, binders such as starches, and/or
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active compounds are dissolved
or suspended in suitable liquids, such as fatty oils, liquid
paraffin, or liquid polyethylene glycols. In some embodiments,
stabilizers are added.
In certain embodiments, delivery systems for pharmaceutical
compounds may be employed, such as, for example, liposomes and
emulsions. In certain embodiments, compositions provided herein can
also include an mucoadhesive polymer, selected from among, for
example, carboxymethylcellulose, carbomer (acrylic acid polymer),
poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic
acid/butyl acrylate copolymer, sodium alginate and dextran.
Combination Treatment
The compounds according to Formula I or Formula Ia may be used in
combination with one or more antibiotics in the treatment of
bacterial infections. Such antibiotics may be administered, by a
route and in an amount commonly used therefore, contemporaneously
or sequentially with a compound of Formula I or Ia. When a compound
of Formula I or Ia is used contemporaneously with one or more
antibiotic, a pharmaceutical composition in unit dosage form
containing such other drugs and the compound of the present
invention is preferred. However, the combination therapy may also
include therapies in which the compound of Formula I or Ia and one
or more antibiotics are administered on different overlapping
schedules. It is also contemplated that when used in combination
with one or more antibiotics, the antibiotics may be used in lower
doses than when each is used singly.
Accordingly, the pharmaceutical compositions of the present
invention also include those that contain one or more antibiotics,
in addition to a compound according to Formula I or Formula Ia. In
some embodiments, a pharmaceutical composition comprising a
compound of Formula I or Ia further comprises a beta-lactam
antibiotic. In certain embodiments, the beta-lactam antibiotic is a
penicillin, cephalosporin, carbapenem, monobactam, bridged
monobactam, or a combination thereof.
The above combinations include combinations of a compound of
Formula I or Ia not only with one antibiotic, but also with two or
more antibiotics. Likewise, compounds of Formula I or Ia, either in
combination with an antibiotic or by themselves, may be used in
combination with other drugs that are used in the prevention,
treatment, control, amelioration, or reduction of risk of bacterial
infections or conditions associated with bacterial infections. Such
other drugs may be administered, by a route and in an amount
commonly used therefore, contemporaneously or sequentially with a
compound of Formula I or Ia. When a compound of Formula I or Ia is
used contemporaneously with one or more other drugs, a
pharmaceutical composition containing such other drugs in addition
to the compound of the present invention is preferred. Accordingly,
the pharmaceutical compositions of the present invention also
include those that also contain one or more other active
ingredients, in addition to a compound of Formula I or Ia. The
weight ratio of the compound of Formula I or Ia to the second
active ingredient may be varied and will depend upon the effective
dose of each ingredient. Generally, an effective dose of each will
be used.
In some embodiments, the compounds according to Formula I or
Formula Ia are used in combination with one or more antibiotics in
the treatment of bacterial infections. In certain embodiments, the
bacterial infection is an upper or lower respiratory tract
infection, a urinary tract infection, an intra-abdominal infection,
or a skin infection. In some embodiments, the one or more
antibiotics are selected from .beta.-lactam antibiotics.
.beta.-Lactam antibiotics include, but are not limited to,
penicillins, penems, carbapenems, cephalosporins, cephamycins,
monobactams, or combinations thereof. Penicillins include, but are
not limited to, amoxicillin, ampicillin, azidocillin, azlocillin,
bacampicillin, benzathine benzylpenicillin, benzathine
phenoxymethylpenicillin, benzylpenicillin (G), carbenicillin,
carindacillin, clometocillin, cloxacillin, dicloxacillin,
epicillin, flucloxacillin, hetacillin, mecillinam, metampicillin,
meticillin, mezlocillin, nafcillin, oxacillin, penamecillin,
pheneticillin, phenoxymethylpenicillin (V), piperacillin,
pivampicillin, pivmecillinam, procaine benzylpenicillin,
propicillin, sulbenicillin, talampicillin, temocillin, ticarcillin.
Penems include, but are not limited to, faropenem. Carbapenems
include, but are not limited to, biapenem, ertapenem, doripenem,
imipenem, meropenem, panipenem. Cephalosprins/Cephamycins include,
but are not limited to, cefacetrile, cefaclor, cefadroxil,
cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin,
cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone,
cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir,
cefditoren, cefepime, cefetamet, cefixime, cefmenoxime,
cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone,
ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin,
cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime,
cefprozil, cefquinome, cefquinome, cefradine, cefroxadine,
cefsulodin, ceftaroline fosamil, ceftazidime, cefteram, ceftezole,
ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole,
ceftriaxone, cefuroxime, cefuzonam, flomoxef, latamoxef,
loracarbef. Monobactams include, but are not limited to, aztreonam,
carumonam, nocardicin A, tigemonam.
Administration of Pharmaceutical Composition
Suitable routes of administration include, but are not limited to,
oral, intravenous, rectal, aerosol, parenteral, ophthalmic,
pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and
topical administration. In addition, by way of example only,
parenteral delivery includes intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intralymphatic, and
intranasal injections.
In some embodiments, compounds of Formula I or Formula Ia and
compositions thereof are administered in any suitable manner. The
manner of administration can be chosen based on, for example,
whether local or systemic treatment is desired, and on the area to
be treated. For example, the compositions can be administered
orally, parenterally (e.g., intravenous, subcutaneous,
intraperitoneal, or intramuscular injection), by inhalation,
extracorporeally, topically (including transdermally,
ophthalmically, vaginally, rectally, intranasally) or the like.
Parenteral administration of the composition, if used, is generally
characterized by injection. Injectables can be prepared in
conventional forms, either as liquid solutions or suspensions,
solid forms suitable for solution of suspension in liquid prior to
injection, or as emulsions. A more recently revised approach for
parenteral administration involves use of a slow release or
sustained release system such that a constant dosage is
maintained.
Assays for Antibacterial Activity
Assays for the inhibition of beta-lactamase activity are well known
in the art. For instance, the ability of a compound to inhibit
beta-lactamase activity in a standard enzyme inhibition assay may
be used (see, e.g., Page, Biochem J, 295:295-304 (1993)).
Beta-lactamases for use in such assays may be purified from
bacterial sources or preferably, are produced by recombinant DNA
techniques, since genes and cDNA clones coding for many
beta-lactamases are known (see, e g, Cartwright & Waley,
Biochem J 221:505-12 (1984)).
Alternatively, the sensitivity of bacteria known, or engineered, to
produce a beta-lactamase to an inhibitor may be determined. Other
bacterial inhibition assays include agar disk diffusion and agar
dilution (see, e.g, Traub & Leonhard, Chemotherapy 43 159-67
(1997)). Thus, a beta-lactamase may be inhibited by contacting the
beta-lactamase enzyme with an effective amount of an inventive
compound or by contacting bacteria that produce the beta-lactamase
enzymes with an effective amount of such a compound so that the
beta-lactamase in the bacteria is contacted with the inhibitor. The
contacting may take place in vitro or in vivo. "Contacting" means
that the beta-lactamase and the inhibitor are brought together so
that the inhibitor can bind to the beta-lactamase. Amounts of a
compound effective to inhibit a beta-lactamase may be determined
empirically, and making such determinations is within the skill in
the art. Inhibition includes both reduction and elimination of
beta-lactamase activity.
Methods
The present disclosure also provides methods for inhibiting
bacterial growth, by, e.g., reducing bacterial resistance to a
.beta.-lactam antibiotic, such methods comprising contacting a
bacterial cell culture, or a bacterially infected cell culture,
tissue, or organism, with a beta-lactamase inhibitor described
herein. Preferably, the bacteria to be inhibited by administration
of a beta-lactamase inhibitor of Formula I or Ia are bacteria that
are resistant to beta-lactam antibiotics. The term "resistant" is
well-understood by those of ordinary skill in the art (see, e g
Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772
(1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 30
1120-1126 (1995)).
These methods are useful for inhibiting bacterial growth in a
variety of contexts. In certain embodiments, a compound of Formula
I or Ia is administered to an experimental cell culture in vitro to
prevent the growth of beta-lactam resistant bacteria. In certain
other embodiments, a compound of Formula I or Ia is administered to
a mammal, including a human to prevent the growth of beta-lactam
resistant bacteria in vivo. The method according to this embodiment
comprises administering a therapeutically effective amount of a
beta-lactamase inhibitor for a therapeutically effective period of
time to a mammal, including a human. Preferably, the beta-lactamase
inhibitor is administered in the form of a pharmaceutical
composition as described above. In some embodiments, a beta-lactam
antibiotic is co-administered with the beta-lactamase inhibitor as
described above.
In another aspect provided herein are methods of treating a
bacterial infection, which method comprises administering to a
subject a pharmaceutical composition comprising a compound of
Formula I or Formula Ia, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient. In some
embodiments, the methods of treating a bacterial infection in a
subject comprises administering to the subject a pharmaceutical
composition as described herein, optionally in combination with a
beta-lactam antibiotic. In some embodiments, the bacterial
infection is an upper or lower respiratory tract infection, a
urinary tract infection, an intra-abdominal infection, or a skin
infection.
In some embodiments, the infection that is treated or prevented
comprises a bacteria that includes Pseudomonas aeruginosa,
Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas
alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia,
Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli,
Citrobacter freundii, Salmonella typhimurium, Salmonella typhi,
Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae,
Shigella flexneri, Shigella sonnei, Enterobacter cloacae,
Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca,
Serratia marcescens, Francisella tularensis, Morganella morganii,
Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens,
Providencia rettgeri, Providencia stuartii, Acinetobacter
baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus,
Yersinia enterocolitica, Yersinia pestis, Yersinia
pseudotuberculosis, Yersinia intermedia, Bordetella pertussis,
Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus
influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus,
Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella
multocida, Pasteurella haemolytica, Branhamella catarrhalis,
Helicobacter pylori, Campylobacter fetus, Campylobacterjejuni,
Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio
parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,
Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,
Gardnerella vaginalis, Bacteroides fragilis, Bacteroides
distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus,
Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides
uniformis, Bacteroides eggerthii, Bacteroides splanchnicus,
Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium
avium, Mycobacterium intracellulare, Mycobacterium leprae,
Corynebacterium diphtheriae, Corynebacterium ulcerans,
Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus
pyogenes, Enterococcusfaecalis, Enterococcusfaecium, Staphylococcus
aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus,
Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus,
Staphylococcus haemolyticus, Staphylococcus hominis, or
Staphylococcus saccharolyticus.
In some embodiments, the infection that is treated or prevented
comprises a bacteria that includes Pseudomonas aeruginosa,
Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia
coli, Citrobacter freundii, Salmonella typhimurium, Salmonella
typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella
dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter
cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella
oxytoca, Serratia marcescens, Acinetobacter calcoaceticus,
Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia
pestis, Yersinia pseudotuberculosis, Yersinia intermedia,
Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus
haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori,
Campylobacter fetus, Campylobacter jejuni, Campylobacter coli,
Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,
Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria
meningitidis, Moraxella, Bacteroides fragilis, Bacteroides
vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron,
Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides
splanchnicus.
EXAMPLES
List of Abbreviations
As used above, and throughout the description of the invention, the
following abbreviations, unless otherwise indicated, shall be
understood to have the following meanings:
ACN acetonitrile
Bn benzyl
BOC or Boc tert-butyl carbamate
BOP benzotriazol-1-yl-oxytris (dimethylamino) phosphonium
t-Bu tert-butyl
Cbz benzyl carbamate
Cy Cyclohexyl
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCC dicyclohexylcarbodiimide
DCM dichloromethane (CH.sub.2Cl.sub.2)
DIC 1,3-diisopropylcarbodiimide
DEAD diethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIEA diisopropylethylamine
DMAP 4-(N,N-dimethylamino)pyridine
DMP reagent Dess-Martin Periodinane reagent
DMF dimethylformamide
DMA N,N-Dimethylacetamide
DME 1,2-Dimethoxy-ethane
DMSO dimethylsulfoxide
Dppf 1,1'-Bis(diphenylphosphino)ferrocene
EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl
eq equivalent(s)
Et ethyl
Et.sub.2O diethyl ether
EtOH ethanol
EtOAc ethyl acetate
HOAt 1-hydroxy-7-azabenzotriazole
HOBT 1-hydroxybenztriazole
HOSu N-hydroxysuccinamide
HPLC high performance liquid chromatography
LAH lithium aluminum anhydride
LC liquid chromatography
Me methyl
MeI methyliodide
MeOH methanol
MOMCl methoxymethylchloride
MOM methoxymethyl
MS mass spectroscopy
NMP N-methyl-pyrrolidin-2-one
NMR nuclear magnetic resonance
PyBOP benzotriazole-1-yl-oxytris-pyrrolidino-phosphonium
Hexafluorophosphate
SPHOS 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl
TBD 1,5,7-triazabicyclo[4.4.0]-dec-5-ene
RP-HPLC reverse phase-high pressure liquid chromatography
TBS tert-butyldimethylsilyl
TBSCl tert-butyldimethylsilyl chloride
TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
TEOC 2-Trimethylsilylethyl Carbamate
TFA trifluoroacetic acid
Tf.sub.2O triflate anhydride
TMG 1,1,3,3-Tetramethylguanidine
THF tetrahydrofuran
THP tetrahydropyran
TLC thin layer chromatography
XPHOS 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
General Examples for the Preparation of Compounds of the
Invention
The starting materials and intermediates for the compounds of this
invention may be prepared by the application or adaptation of the
methods described below, their obvious chemical equivalents, or,
for example, as described in literature such as The Science of
Synthesis, Volumes 1-8. Editors E. M. Carreira et al. Thieme
publishers (2001-2008). Details of reagent and reaction options are
also available by structure and reaction searches using commercial
computer search engines such as Scifinder (www.cas.org) or Reaxys
(www.reaxys.com).
Certain compounds of the invention (I) (SCHEME 1) are prepared from
the corresponding functional-group-protected boronic acid esters
(II) by treatment with a Lewis acid such as BCl.sub.3, in a solvent
such as dichloromethane, at a temperature between -78.degree. C.
and 0.degree. C. followed by an aqueous quench.
##STR00023##
Alternatively, (I) is obtained from (II) by treatment of (II) with
aqueous hydrochloric acid (around 3-5 Molar) in dioxane at a
temperature between room temperature and 100.degree. C.
The requisite boronic acid esters (II) are obtained (SCHEME 2) by
coupling of amine (III) with (carboxylic or sulphonic) acid (IV).
This transformation is effected by first activating the acid
functionality as an acid chloride, anhydride or reactive ester (Va,
Vb or Vc), followed by treatment of the activated substrate with
(III) in a solvent such as DMF, DMA, NMP, THF or dichloromethane
(or a mixture thereof) at about room temperature, usually in the
presence of a non-nucleophilic base such as 4-methyl-morpholine,
triethylamine or diisopropylethylamine.
##STR00024##
Formation of the acid chloride (Va) involves treatment of (IV) with
a chlorinating agent such as thionyl chloride, phosphorous
pentachloride or oxalyl chloride, in a solvent such as
dichloromethane, in the presence of a catalyst such as DMF, at
around room temperature. In certain cases, DMF is also used as a
co-solvent. Formation of the anhydride (Vb) (Z is C.dbd.O) involves
treatment of (IV) with a sterically hindered acid chloride or
chloroformate, such as trimethylacetyl chloride or
isopropylchloroformate, in an inert solvent such as
dichloromethane, in the presence of a non-nucleophilic base, such
as triethylamine or diisopropylamine at room temperature or below.
Formation of the activated ester (Vc) involves treatment of (IV)
with an activating reagent system such as EDCI, DCC/HOBt, HATU, BOP
reagents or TBTU, in a solvent such as DMF, DMA, NMP or
dichloromethane at room temperature or below (International Journal
of Pharmaceutical Sciences Review and Research (2011), 8(1),
108-119).
In certain instances (SCHEME 3), (II) is prepared from the
.alpha.-bromo or chloro-acyl amino intermediate (VI) by treatment
with a suitable heterocyclylamine (VII) in a solvent such as THF in
the presence of a base such as potassium carbonate.
##STR00025##
Intermediate (VI) is prepared from (III) by treatment with
bromoacetyl bromide or chloroacetyl chloride in a solvent such as
THF at a temperature between -20.degree. C. and room
temperature.
The requisite acids (IV) and amines (VII) are prepared by a number
of different reaction sequences. While there are common themes and
strategies among the illustrative examples cited below, the
selection of an appropriate reaction sequence (including protecting
group requirements) is dictated by the nature and arrangement of
the functionality present in the target molecule and, therefore,
may involve obvious adaptations of the illustrated methods in order
to be applied in a particular case.
In the case where HetA is connected to (CR.sup.1R.sup.2).sub.m via
a ring nitrogen atom and Y.sub.1 is connected to HetA through an
amino functionality, the requisite acids (IV) and amines (VII) are
conveniently prepared from an appropriately
substituted-heterocyclic ketone (VIII) (SCHEME 4). For example,
treatment of (VIII) with a suitable amine (IX) in the presence of a
reducing agent such as sodium tri-acetoxyborohydride, sodium
cyanoborohydride or sodium borohydride in a solvent such as
dichloromethane, 1,2-dichloro-ethane, THF, methanol, acetic acid or
a mixture thereof, at a temperature around room temperature gives
the carbamate protected heterocycle (X). In the case where the use
of a primary amine (IX, R.sup.5.dbd.H) is called for, (X) can also
be prepared by treatment of an equimolar mixture of (VIII) and (IX,
R.sup.5.dbd.H) with a Lewis acid/dessicant, such as Ti(OEt).sub.4,
in a solvent such as dichloromethane or 1,2-dichloroethane, at room
temperature or above to provide the intermediate imine. This is
followed by reduction of the imine with sodium borohydride, in a
solvent such as methanol, at a temperature between -78.degree. C.
and room temperature
##STR00026##
Acid (IV) is obtained from heterocycle (X) by formal hydrolysis of
the carbamate functionality followed by derivitization of the
resulting amine (VII) (SCHEME 5). The reaction conditions employed
to cleave the carbamate depend on the type of carbamate used. In
the case of a t-butyl carbamate, cleavage is effected by treatment
with an acid such as trifluoroacetic acid in dichloromethane at
around room temperature or with HCl in a solvent such as ethyl
acetate, ether or 1,4 dioxane. In the case of a benzyl carbamate,
cleavage is achieved by hydrogenolysis at around atmospheric
pressure, using a catalyst such as palladium on carbon in a solvent
such as ethyl acetate, methanol, THF or a combination thereof.
Other carbamate protecting groups can also be used, such as allyl,
2-trimethylsilyl-ethyl or 2,2,2-trichloroethyl. In these cases,
conversion of the carbamate to the corresponding amine is achieved
using the standard deprotection procedures in the literature
(Greene's Protective Groups in Organic Synthesis. Fourth Edition.
John Wiley & Sons, Inc. 2006). It should be understood that the
amine functionality in Y.sub.1 may also be protected as a carbamate
during this sequence (i.e. R.sup.5.dbd.CO.sub.2R') and that this
protecting group should be selected to be orthogonal to the
carbamate protecting the HetA amine functionality.
##STR00027##
For an example of the preparation of (IV) from (VII) consider the
case of (IV) where m=1, M=a bond, n=0. Treatment of (Xa) (R=benzyl)
with hydrogen in the presence of a catalyst such as palladium on
carbon in a solvent such as methanol provides the heterocyclic
amine (VII). Condensation of (VII) with an appropriate
.alpha.-halo-acetic acid ester in a solvent such as acetonitrile,
DMF, DMA or ethanol, in the presence of a non nucleophilic base
such as diisopropylethylamine, triethylamine or potassium carbonate
furnishes the ester (XI). Ester hydrolysis by brief treatment with
an aqueous base such as sodium hydroxide or lithium hydroxide in a
solvent such as ethanol or THF/methanol provides the acid (IV).
For the case of (IV) where m=2, M=a bond, n=0, treatment of (VII)
with an appropriate .alpha.,.beta.-unsaturated ester (XII) in the
presence of a catalyst such as potassium carbonate, cesium fluoride
(Monatshefte fuer Chemie, (2011), 142(10), 1055-1059) cerium
ammonium nitrate (Synlett, (2006), 10, 1549-1553) copper acetate
(Synlett, (2003), 15, 2425-2427) in a solvent such as DMA or
ethanol or water yields (XIII). Hydrolysis of the ester group in
(XIII), as described above, provides the acid (IV).
##STR00028##
In an alternative approach to systems wherein HetA is connected to
(CR.sup.1R.sup.2).sub.m via a ring nitrogen atom and Y.sub.1 is
connected to HetA through an amino functionality, the requisite
acids (IV) and amines (VII) are prepared (SCHEME 6) by treatment of
ketone (VIII) with a reducing agent, such as sodium borohydride in
methanol at around 0.degree. C. or L-selectride in THF, at a
temperature between -78.degree. C. and room temperature to give
alcohol (XIV). Treatment of the alcohol (XIV) with methanesulfonyl
chloride or p-toluene-sulfonyl chloride, in the presence of a non
nucleophilic base, such as triethylamine or DIEA, in a solvent such
as dichloromethane or pyridine, at around 0.degree. C. provides the
corresponding sulfonate ester (XV). Displacement of the sulfonate
group with azide by treatment of (XV) with sodium azide or a
tetra-alkylammonium azide in a solvent such as DMA, DMF, NMP,
acetonitrile or DMSO, at a temperature between room temperature and
120.degree. C., yields the azide (XVI). Reduction of the azide with
triphenylphosphine and water in THF at around room temperature
(Staudinger reaction) yields the primary amine (XVII). Further
derivatization of (XVII), where appropriate, can be accomplished by
reductive amination with an appropriate aldehyde or ketone, using
conditions already described to give (XX).
Alternatively, formation of the N-BOC derivative of (XVII) by
treatment with Boc.sub.2O, in the presence of a non nucleophilic
base such as triethylamine or DIEA, in a solvent such as
dichloromethane, at around room temperature gives carbamate
(XVIII). Treatment of (XVIII) with an alkyl halide or sulphonate in
the presence of a base, such as sodium hydride, potassium carbonate
or tetramethylguanidine, in a solvent such as DMF, DMA, NMP, THF,
DMPU or ethanol (or a mixture thereof), at room temperature or
below, provides (XIX). Cleavage of the BOC group with an acid, such
as TFA in dichloromethane or HCl in dioxane, ethyl acetate or
ether, at around room temperature, provides the secondary amine
(XX). Further derivatization of (XX), where appropriate, can be
accomplished by reductive amination with an appropriate aldehyde or
ketone, using conditions already described, to give (XXI).
Carbamate cleavage in (XXI) provides (VII) and derivitization of
the heterocyclic ring nitrogen as already described, yields
(IV).
##STR00029##
In the case where Y.sub.1 is a guanidine, the guanidino group is
derived from the appropriate heterocyclic primary (XVII) or
secondary (XX) amine (SCHEME 7) by treatment with a reagent such as
1,3-Di-tert-butyloxycarbonyl-S-methylisothiourea, in a solvent such
as DMF, (Synthesis, (2004), 37-42) or pyridine at room temperature
or above, or by treatment with
N,N'Bis-(BOC)-1H-pyrazole-1-carboxamidine in the presence of a base
such as diisopropylethylamine, in a solvent such as DMF or DMA at
around room temperature to give (XXII). Selective cleavage of the
heterocyclic ring carbamate and derivitization of the resulting
heterocyclic amine (VII), as already described, provides the
corresponding acid (IV).
Alternatively, the guanidinyl group can be introduced by treatment
of an appropriate heterocyclic alcohol (XIV) (SCHEME 8) with a
reagent such as BOC-guanidine, in the presence of
triphenylphosphine and diethyl-azo-dicarboxylate, in a solvent such
as THF (Mitsunobu conditions: Chemical Reviews, (2009), 109,
2551-2651) to give (XXIII) directly. Benzyl carbamate cleavage
provides (VII) which is processed to yield (IV) as already
described.
##STR00030##
In the case where Y.sub.1 is an amidine linked to HetA through
nitrogen, the requisite acids (SCHEME 9) are prepared from the
appropriate primary (XVII) or secondary amine (XX) by treatment
with a suitable alkyl thioimidate, such as the
2-napthylmethylthioimidate derivative (XXIV), in a solvent such as
ethanol at a temperature between 0.degree. C. and room temperature
(Tetrahedron Letters, (1997), 38(2), 179-182) to give (XXV).
Protection of the amidine (XXV) as an orthogonal carbamate
derivative such as BOC is effected under standard conditions (BOC
anhydride/triethylamine in methanol) to give (XXVI). Selective
cleavage of the heterocyclic ring carbamate functionality and
derivitization of the heterocyclic amine (VII), as already
described, provides the corresponding acid (IV).
##STR00031##
In the case where Y.sub.1 is an amidine linked to HetA through
carbon (SCHEME 10), the amidine functionality is introduced by
conversion of an appropriate heterocyclic ketone (VIII) to the
corresponding exocyclic nitrile (XXVII) by treatment with
toluenesulfonyl-methylisocyanide (Journal of Organic Chemistry
(1977), 42(19), 3114-18) in the presence of a base such as
KOBu.sup.t in a solvent such as DMSO or DME containing about 2% of
t-butanol or ethanol at a temperature between 0.degree. C. and
50.degree. C. Treatment of (XXVII) with HCl in methanol to form the
corresponding imidate ester (XXVIII) is followed by reaction of
this intermediate with an appropriate amine (XXIX) in a solvent
such as methanol or THF at around room temperature to give the
amidine (XXX). Protection of the amidine functionality as a BOC
derivative (XXXI) is accomplished by treatment of (XXX) with BOC
anhydride in the presence of a base such as triethylamine in a
solvent such as methanol at a temperature between room temperature
and 60.degree. C. Removal of the Cbz group, as previously
described, furnishes the heterocyclic amine (VII). (VII) is
processed to the corresponding acid (IV) as already described.
In certain cases, it is convenient to effect direct amidine
formation from the nitrile (XXVII) (SCHEME 10) using a suitable
methyl-chloroaluminum amide (XXXII), in a solvent such as toluene
at around 80.degree. C. (Tetrahedron Letters, (1990), 31(14),
1969-1972).
##STR00032##
##STR00033##
In the case where R.sup.5.dbd.H (SCHEME 11), the amidine
functionality can also be introduced by treatment of the
appropriate carbocyclic nitrile (XXXIII) with hydroxylamine or an
O-alkyl-hydroxylamine to give the N-hydroxyl-(or alkoxy)-amidine
(XXXIV). This is followed by N--O bond cleavage by catalytic
hydrogenolysis to provide the amidine (XXXV). Benzyl carbamate
derivitization of the amidine functionality in (XXXV) by treatment
with Cbz chloride in the presence of a base such as DIEA in a
solvent such as dichloromethane or by treatment with Cbz chloride
in a solvent such as aqueous THF or aqueous 1,4-dioxane in the
presence of a base such as sodium hydroxide provides (XXXVI).
Cleavage of the heterocyclic ring carbamate yields (VII) which is
further processed to provide acid (IV) as previously described.
In the case where Y.sub.1 is a nitrogen substituted methylene
group, the requisite amines (VII) and acids (IV) (SCHEME 12) are
prepared from the appropriate heterocyclic-ketones (VIII) by
conversion of the ketone functionality into, first, the
corresponding hydroxyl-methyl derivative by treatment with an
olefination reagent such as methyltriphenylphosphonium bromide in
the presence of sodium hexamethyldisilazide, in a solvent such as
THF at around 0.degree. C. (Wittig reaction) or by treatment with
lithium trimethylsilylmethane/CeCl.sub.3 at around 0.degree. C. to
room temperature, in a solvent such as THF or ether (Peterson
reaction) (Journal of Organic Chemistry, (1987) 52(2), 281-3) or by
reaction with the Petasis modified Tebbe reagent
(dicyclopentadienyl-dimethyltitanium) in THF/toluene at around
60.degree. C. (Journal of the American Chemical Society, (1990),
112 (17) 6392-6394) to give (XXXVII). This is followed by
hydroboration of the exocyclic alkene in (XXXVII) with a reagent
such as borane THF or an alkyl derivative, at around 0.degree. C.,
in a solvent such as THF, followed by oxidative workup with
hydrogen peroxide/NaOH (aq.) to provide (XXXVIII). Conversion of
the hydroxymethyl (XXXVIII) into the functionalized amino-methyl
derivative (XL) can be accomplished by conversion to the
corresponding tosylate, azide and primary amine as described above.
Alternatively, oxidation of (XXXVIII) to the aldehyde (XXXIX)
followed by reductive amination of (XXXIX) with an amine
(R.sup.4R.sup.5NH), as already described, also provides amine (XL).
Conversion of (XL) to the requisite amine (VII) and or acid (IV) is
accomplished by side chain modification as previously
described.
##STR00034##
Alternatively, aminomethylene-substituted heterocycles are also
prepared from the appropriate heterocyclic nitriles (XXXIII)
(SCHEME 13) by treatment with a reagent such as nickel chloride
hexahydrate with sodium borohydride in a solvent such as methanol
(J. Am. Chem. Soc., (2006) 128, 15996-15997) to give the primary
amine (XLI). Derivitization of the primary amine as previously
outlined provides (XL) which is, in turn, processed to give (VII)
and (IV) as described above.
##STR00035##
In the case where Y.sub.1 is an optionally substituted amino-ethyl
group, the requisite amine (VII) and acids (IV) are prepared from
the corresponding heterocyclic ketone (VIIIb) (SCHEME 14) by
treatment with an appropriate trialkyl-phosphonoacetate, such as
triethylphosphonoacetate, in a solvent such as THF, in the presence
of a base such as sodium hydride, at a temperature between about
-5.degree. C. and room temperature to give the corresponding
.alpha.,.beta.-unsaturated ester (XLII) (Liebigs Annalen/Recueil,
(1997), 7, 1283-1301). Reduction of the enone double bond is
achieved by treatment of (XLII) with a heterogeneous Pd, Rh or Pt
catalyst, such as 10% Pd on carbon, under an atmosphere of hydrogen
gas (1-4 atm), in a solvent such as ethyl acetate, methanol or THF
(or a mixture thereof) at room temperature to 70 OC to give the
saturated ester (XLIII). Alternatively, in certain cases,
unsaturated-ester (XLII) may be reduced by treatment with excess
magnesium, in a solvent such as methanol, at around room
temperature (Tetrahedron Letters, (1986); 27(21), 2409-2410) to
provide (XLIII). The ester functionality in (XLIII) is hydrolyzed
to give the corresponding acid (XLIV) by brief treatment with a
base such as sodium hydroxide or lithium hydroxide, in a solvent
such as THF/methanol/water at around room temperature. Selective
reduction of the acid functionality in (XLIV) by treatment with
borane in a solvent such as THF at a temperature between 0.degree.
C. and room temperature provides primary alcohol (XLV). Alcohol
(XLV) is processed to the optionally substituted amine (XLVIII) via
the corresponding tosylate, azide and primary amine (XLVI) or by
oxidation to the corresponding aldehyde (XLVII) and reductive
amination using the reagent systems already outlined. Deprotection
of the heterocyclic amine in (XLVIII) yields (VII) which is
converted to the corresponding acid (IV) as already described.
##STR00036##
In the case where Y.sub.1 and Y.sub.2 are each linked to HetA
through a nitrogen atom and Y.sub.1 and Y.sub.2 are positioned
vicinally to each other on the heterocycle, the requisite amines
(VII) and acids (IV) (SCHEME 15) are prepared from the appropriate
heterocyclic olefins (XLIX). For example, treatment of (XLIX) with
sodium azide, in the presence of a mild oxidant, such as
Mn(OAc).sub.3(H.sub.2O).sub.2 and an acid such as acetic acid or
trifluoroacetic acid, in a solvent such as acetonitrile, at a
temperature between -30.degree. C. and 0.degree. C. provides the
diazide (L) in predominantly the trans isomer configuration
(Synthetic Communications, 28(10), 1913-1922; 1998). Subsequent
reduction of the bis-azide by treatment with a reducing agent, such
as triphenylphosphine, in a solvent such as THF, followed by in
situ hydrolysis of the intermediate aza-phosphorane by the addition
of excess water yields the bis-amine (LI). This bis-primary-amine
(LI) is protected as a BOC or other suitable N-protected derivative
(Greene's Protective Groups in Organic Synthesis; 4th Edition: John
Wiley & Sons, Inc., 2006). For example, treatment of (LI) with
an appropriate anhydride or chloroformate, in the presence of a
base such as triethylamine, in a solvent such as THF or
dichloromethane, at around room temperature provides the carbamate
intermediate (LII). Where appropriate, the carbamate is further
derivatized by treatment with a suitable alkylating agent, in the
presence of a base, such as K.sub.2CO.sub.3, in a solvent such as
DMF, DMA, or acetonitrile to give (LIII). Removal of the carbamate
protecting group to give (LIV), followed by treatment of the
resulting secondary amine with an aldehyde or ketone in the
presence of a reducing agent such as sodium borohydride, sodium
cyanoborohydride or sodium triacetoxyborohydride in a solvent such
as dichloromethane, 1,2-dichloroethane, methanol or THF at around
room temperature provides (LV). Processing of (LV), as already
described, yields (VII) and (IV).
##STR00037##
Alternatively, treatment of the appropriate heterocyclic olefin
(XLIX) (SCHEME 16) with an oxidant such as meta-chloroperbenzoic
acid in a solvent such as dichloromethane at around 0.degree. C.
provides the corresponding cyclic epoxide (LVI). Ring opening of
the epoxide by treatment with sodium azide and ammonium chloride in
a solvent such as ethanol, poly-ethylene-glycol, or DMF/water at a
temperature between room temperature and 80.degree. C., provides
the trans hydroxyl azide (LVII). Reaction of (LVII) with
methanesulfonyl chloride in pyridine at around 0.degree. C. yields
the mesylate (LVIII). Treatment of (LVIII) with tetrabutylammonium
azide in a solvent such as toluene provides the cis-oriented bis
azide (LIX). Processing of intermediate (LIX) is carried out as
previously described to provide (LX), amine (VII) and acid
(IV).
##STR00038##
In the case where Y.sub.1 is linked to HetA through a nitrogen
atom:Y.sub.2 is an optionally substituted aminomethyl and Y.sub.1
and Y.sub.2 are positioned vicinally to each other on the
heterocycle, the requisite amines (VII) and acids (IV) (SCHEME 17)
are prepared from the appropriate .alpha.-azido-alcohol (LVII) by
processing the azide as previously described to give aminoalcohol
(LXI). Treatment of (LXI) with methanesulfonyl chloride in pyridine
at around 0.degree. C. yields the mesylate (LXII). Displacement of
the mesylate with cyanide by treatment of (LXII) with
tetrabutylammonium cyanide in a solvent such as acetonitrile
(Bioorg. Med. Chem. Lett., (2009), 19, 1084-1088) yields (LXIII).
Reduction of the nitrile in (LXIII) by treatment with sodium
borohydride in the presence of a catalyst such as nickel chloride
hexahydrate (J. Am. Chem. Soc., (2006), 128, 15996-15997) provides
(LXIV). Derivitization of the primary amine in (LXIV) as previously
outlined yields (LXV). This intermediate is, in turn, processed to
provide (VII) and (IV) as previously described.
##STR00039##
In the case where Y.sub.1 is linked to HetA through a nitrogen
atom:Y.sub.2 is an optionally substituted aminoethyl and Y.sub.1
and Y.sub.2 are positioned vicinally to each other on the
heterocycle, the requisite amines (VI) and acids (IV) (SCHEME 18)
are prepared from the appropriate heterocyclic ketone (VIII) by
reaction with a base such as LDA in a solvent such as THF, HMPA or
THF/TBTU at a temperature between -78.degree. C. and 0.degree. C.
to form the corresponding enolate in situ. This is followed by
treatment of the enolate with an allylic bromide to give (LXVI).
Derivitization of the heterocyclic ketone as previously outlined
yields the heterocyclic amine (LXVII). Oxidation of the olefin by
treatment with catalytic amounts of osmium tetroxide (Org. Synth.
Oxid. Met. Compd. (1986), 633-93. Publisher: Plenum, N.Y.) in the
presence of a co-oxidant such as N-methyl morpholine N-oxide, in a
solvent such as tert-butanol/water to yield the corresponding
di-hydroxy-derivative (LXVIII). This diol is then oxidatively
cleaved using sodium periodate, in a solvent such as THF/water, at
around room temperature, to give carbonyl compound (LXIX). This
intermediate is processed as previously described to give amine
(LXX). Removal of the heterocyclic nitrogen carbamate protecting
group yields (VII) which is further derivitized to yield (IV) as
previously described.
##STR00040##
In the case where Y.sub.1 is attached to HetA through a ring
nitrogen, the requisite acids (IV) (SCHEME 19) are prepared from
heterocyclic ketone (VIII) by elaboration of the ketone
functionality to (CR.sup.1R.sup.2).sub.mCO.sub.2H and
derivitization of the heterocyclic ring nitrogen as previously
described for amine (NR.sup.4R.sup.5), amidinyl
(R.sup.5C(.dbd.NR.sup.4)-- or guanidinyl
(R.sup.4R.sup.5NC(.dbd.NR.sup.4)--) above. For example, in the case
where M=bond and m=1 (SCHEME 19), (IV) is prepared from (VIII) by
treatment with triethylphosphonoacetate as described above to give
enone (LXXI). Reduction of the double bond in (LXXI) with
concommitant cleavage of the benzyl carbamate is accomplished by
treatment with hydrogen in the presence of a catalyst such as
palladium on carbon in a solvent such as methanol, ethanol, ethyl
acetate or THF to provide the amine (LXXII). Processing of the
amino functionality in (LXXII), as previously outlined, provides
the ring amino substituted derivatives (LXXIII). Finally, (LXXIII)
is converted to the requisite acid (IV) by brief treatment with
aqueous base as previously described.
##STR00041##
In the case where M=bond and m=0, the requisite acids (IV) (SCHEME
20) are prepared from aldehyde (XXXIX). Oxidation of (XXXIX) is
accomplished by treatment with sodium chlorite/sodium
dihydrogenphosphate in the presence of tetramethylethylene, in a
solvent such as t-butanol/water at around room temperature (Journal
of Organic Chemistry, (1980), 45, 4825). This is followed by
esterification of the intermediate acid with methyl iodide in a
solvent such as DMF in the presence of a base such as potassium
carbonate to yield ester (LXXIII). Removal of the heterocyclic
t-butyl carbonate protecting group under standard conditions yields
secondary amine (LXXIV). Processing of (LXXIV) to the derivitized
intermediates (LXXV) is accomplished as previously described.
(LXXV) is converted to the requisite acid (IV) by ester hydrolysis
under standard conditions.
##STR00042##
In the case where M=bond and m=2, the requisite acids (IV) (SCHEME
21) are prepared from aldehyde (XXXIX) by treatment with a
trialkylphosphonoacetate reagent as previously described to provide
ester (LXXVI). Hydrogenation of the double bond of the enone using
hydrogen in the presence of a palladium catalyst as previously
described yields (LXXVII). Cleavage of the t-butyl carbamate then
provides secondary amine (LXXVIII). Subsequent processing of
(LXXVIII) via (LXXIX) to yield (IV) is accomplished as outlined
above for m=1.
##STR00043##
In the case where M=O, m=1, the requisite acids (IV) (SCHEME 22)
are prepared from alcohol (XIV) by condensation with ethyl
diazoacetate in the presence of a catalyst such as Rh(acac) dimer
in a solvent such as dichloromethane to provide the alkoxyacetate
derivative (LXXX). Cleavage of the heterocyclic ring nitrogen
protected carbamate under standard conditions yields (LXXXI). This
intermediate is processed to acid (IV) by amine derivitization and
ester hydrolysis as previously outlined.
##STR00044##
In the case where M=NR.sup.4, m=1, the requisite acids (IV) (SCHEME
23) are prepared from ketone (VIII) by reductive amination with a
suitable .alpha.-amino acid ester (LXXXII) to give (LXXXIII).
Subsequent cleavage of the heterocyclic nitrogen carbamate and
processing of the resulting secondary amine as described above
provides ester (LXXXIV). Hydrolysis of the ester under standard
conditions yields (IV).
##STR00045##
In the case where both Y.sub.1 and
M(CR.sup.1R.sup.2).sub.mCO.sub.2H are each connected to HetA at
carbon atoms of HetA (SCHEME 24), the requisite acids (IV) can be
prepared from a suitable protected keto-alcohol such as (LXXXV) by
elaboration of the ketone functionality into
M(CR.sup.1R.sup.2).sub.mCO.sub.2R by adaptation of the methods
described above to give (LXXXVI). This sequence is followed by
elaboration of the protected alcohol into Y.sub.1 again, following
the methods already outlined for this type of transformation.
##STR00046##
The requisite functionalized heterocycles are known compounds or
are prepared by various synthetic pathways depending on the nature
of the heterocycle in question. For example, in the case where HetA
is a piperidine, Y.sub.1 is connected to HetA through the ring
nitrogen and Y.sub.2 is an optionally substituted aminomethyl
(SCHEME 25), the requisite ketone (VIII) is prepared from amino
aldehyde (LXXXVIII). Imine formation with diphenylmethylamine under
standard conditions affords (LXXXIX). A tandem Mannich-Michael
reaction with Danishefsky's diene (XC) in the presence of a Lewis
acid such as zinc iodide in a solvent such as acetonitrile at a
temperature of 0.degree. C. or lower provides the desired enaminone
which is selectively reduced using a reducing agent such as
L-selectride in a solvent such as THF at a low temperature
(-50.degree. C. or below) to provide the piperidinone (XCI)
(Tetrahedron, (1999) 55, 7601-7612). A standard protecting group
switch, where appropriate by hydrogenolysis and BOC formation
provides (VIII).
##STR00047##
In the case where HetA is a pyrrolidine, Y.sub.1 is connected to
HetA through the ring nitrogen and Y.sub.2 is an optionally
substituted aminomethyl (SCHEME 26), the requisite ketone (VIII) is
prepared from the known hydroxyl proline aldehyde (XCII)
(Tetrahedron, (1991), 47(27), 5051-5070) by reductive amination
with a suitable amine under conditions described previously to give
(XCIII). This is followed by removal of the silyl protecting group
using a reagent such as tetrabutylammonium fluoride in THF at
around room temperature and oxidation of the intermediate alcohol
with Dess-Martin periodinane in dichloromethane at room temperature
to give (VIII).
##STR00048##
In the case where HetA is a pyran ring, the requisite protected
alcohol (LXXXVI) (SCHEME 27) is prepared from the known
2-acetoxy-4-benzyloxy-pyran (Organic Letters, (2008), 10(21),
4907-491) by Lewis acid mediated C--C bond formation using an allyl
silane, vinyl silane, TMS cyanide, silylketene acetal or silyl enol
ether to generate a range of side chains that can be elaborated
into M(CR.sup.1R.sup.2)CO.sub.2R using methods described above.
##STR00049##
##STR00050##
In the case where HetA is a piperidin-2-one and Y.sub.1 is linked
to HetA through an amine functionality (SCHEME 28), the requisite
substituted heterocycles are prepared from the known
4-amino-piperidin-2-one (XCVI) by reductive amination with excess
benzophenone as described above to provide (XCVII). This is
followed by elaboration of the piperidin-one nitrogen to install
the (CR.sup.1R.sup.2).sub.mCO.sub.2R functionality. For example, in
the case where m=2, the requisite side chain is introduced by
treatment of (XCVII) with an acrylate derivative in the presence of
a base such as cesium fluoride and a Lewis acid such as
tetraethoxysilane (Tetrahedron Letters, (1994), 35(12), 1875-8) to
give ester (XCVIII). In the case where m=1, treatment of (XCVII)
with a bromo-acetate derivative in the presence of a base such as
sodium hydride in a solvent such as DMF, DMA or NMP provides
(XCIX). Hydrogenolysis of the N-benzyl groups in (XCVIII) or (XCIX)
using palladium hydroxide in methanol at a hydrogen pressure of 1-4
atm yields the free amines (C) and (CI) respectively. These
intermediates are derivatized as previously described for compound
(XVIII).
In the case where HetA is a pyrrolidin-2-one and Y.sub.1 is linked
to HetA through an amine functionality, the requisite amines (CII)
and (CIII) are prepared (SCHEME 29) as described above for the case
of the piperidin-2-one, except starting with lactams (CIV) (Organic
Letters (2012), 14(1), 218-221 and Journal of Organic Chemistry
(2009), 74(11), 4177-4187).
##STR00051##
In the case where HetA is a piperazin-2-one or
1,4-diazepan-2-one:Y.sub.1 is attached to hetA at N-4 and
(CR.sup.1R.sup.2).sub.m is attached to HetA at N-1 (SCHEME 30), the
requisite functionalized heterocycles are prepared from a suitable
diamine (CV) by treatment with an appropriate .alpha.-keto ester
substrate (CVI) under the reductive amination conditions described
above to give intermediate (CVII). Deprotection of the carbamate
and acid functionality by treatment with an acid such as
trifluoroacetic acid in a solvent such as dichloromethane at around
room temperature gives amino acid (CVIII). Cyclization is affected
by treatment of (CVIII) with a reagent system such as
pyridyldisulfide/triphenylphosphine in a solvent such as toluene at
a temperature between room temperature and reflux to give (CIX).
Elaboration of N-1 to install (CR.sup.1R.sup.2).sub.mCO.sub.2R is
achieved, as previously described for the case of (XCVII), to
provide the requisite intermediates (CXI) and (CXII).
##STR00052##
In the case where HetA is a piperazine or 1,4-diazepane:Y.sub.1 is
attached to HetA at N-1 and (CR.sup.1R.sup.2).sub.m is attached to
HetA at N-4 and Y.sub.2 is an aminomethyl group attached to HetA
and C-2 (SCHEME 31), the requisite functionalized heterocycles are
prepared from the C-2 carboxy-piperazine or 2-carboxy-1,4 diazepane
(CXIII). Differential protection of the heterocyclic ring nitrogens
is achieved using such reagents as
2-(Boc-oxyimino)-2-methylacetonitrile in the presence of
camphorsulfonic acid to install a BOC group selectively at N-4.
This is followed by standard CBZ protection at N-1 (Enantiomer
(2001), 6(6), 343-345) to give (CXIV). Conversion of (CXIV) to the
corresponding Weinreb amide using a reagent such as
N,O-dimethylhydroxylamine hydrochloride with a coupling reagent
such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride and an organic base such as triethylamine and/or
dimethylaminopyridine in a solvent such as dichloromethane affords
(CXV). The activated amide is reduced using a reducing agent such
as sodium borohydride in a solvent such as methanol to provide the
alcohol (CXVI). Reaction (CXVI) with a sulfonyl halide such as
methanesulfonyl chloride with an organic base such as triethylamine
in a solvent such as dichloromethane at room temperature or below
is followed by displacement of the sulfonate with an azide source
such as sodium azide in a solvent such as DMF at room temperature
or higher to yield the azide (CXVIII) (Bioorg. Med. Chem. Lett.,
(2009) 19, 5440-5443). The azide is reduced following one of the
procedures described previously and the resulting primary amine
(CXIX) is derivitized as previously described. Deprotection of the
BOC protecting group provides (CXX).
##STR00053##
##STR00054##
The heterocyclic olefins (such as XLIX) described in this text are
known compounds or are prepared by a range of known synthetic
methods. For example (SCHEME 32), (XLIX) can be prepared from an
acyclic precursor (CXXI) by treatment with one of a range of
Grubb's or Schrock metathesis catalysts (Tetrahedron, (2012), 68(2)
397-421; Organic Letters, (2007), 9(23), 4885-4888; Tetrahedron,
(2004), 60, 7117-7139) in a solvent such as dichloromethane, at
room temperature or above, or in an aqueous PEGs.sub.500 dimethyl
ether solution. These conditions are also suitable for the
construction of heterocyclic olefins (CXXII) where the heteroatom
is not attached to --Y.sub.p or --(CR.sup.1R.sup.2).sub.m.
For a specific example, in the case where HetA is an oxepane ring
linked to (CR.sup.1R.sup.2).sub.m at C-2 and to Y.sub.1 at C-5
(SCHEME 33), the requisite ketone intermediate (CXXIV) can be
prepared from the acyclic precursor (CXXV) (Tetrahedron, (2007),
63(21), 4472-4490) by ring closure metathesis to give (CXXVI)
followed by hydrogenation of the double bond. (CXXV) is, in turn,
prepared by treatment of the secondary alcohol (CXXVII) with
triphenylchloroacetonylphosphorane and olefination of the resulting
phosphorane with formaldehyde.
In the case where Z is a sulfonyl group (SCHEME 34), the requisite
sulfonic acid is prepared from the corresponding activated
carboxylic acid (V) by treatment with sodium hydroxythiopyridone in
a solvent such as dichloromethane, at around room temperature to
yield the Barton ester intermediate (CXXVII). (CXXVII) is treated
with iodoform in CCl.sub.4 under a tungsten UV lamp at around
reflux temperature to provide the de-carboxylative-iodination
product (CXXVIII) (Journal of Organic Chemistry, 75(19), 6489-6501;
2010). Alternatively, treatment of acid (IV) with
iodosobenzene-diacetate and iodine in CCl.sub.4, under a tungsten
UV lamp, at around reflux temperature (Journal of Organic
Chemistry, (1986), 51, 402) provides (CXXVIII) directly. Treatment
of (CXXVIII) with sodium sulfite in aqueous ethanol, isopropanol or
acetone, at a temperature between 60 and 90.degree. C., followed by
acidification yields the sulfonic acid (IV). Alternatively,
treatment of (CXXVIII) with thiourea in acetone, at around
60.degree. C., provides the isothiouronium salt derivative (CXXIX)
(Synthetic Letters, (2010), 7, 1037). Cleavage of (CXXIX) with aq.
sodium thiosulphate gives thiol (CXXX). Treatment of (CXXX) with
performic acid (formic acid and aqueous H.sub.2O.sub.2 at around
0.degree. C. to room temperature) provides (IV).
The requisite amines (III) are prepared according to literature
methods (WO2010/130708).
##STR00055##
Synthetic Examples
##STR00056##
The following preparations of compounds of Formula I or Formula Ia
and intermediates are given to enable those of skill in the art to
more clearly understand and to practice the present invention. They
should not be considered as limiting the scope of the invention,
but merely as illustrative and representative thereof.
Example 1:
3-[2-(4-Amino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00057##
Step 1. Synthesis of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
l)-benzoic acid
A solution of 3-borono-2-methoxybenzoic acid (Combi-Blocks, 7.42 g,
37.9 mmol) and (+)-pinanediol (6.44 g, 37.8 mmol) in
tetrahydrofuran (THF, 56 mL) was stirred at room temperature for 91
h. The solution was concentrated in vacuo and triturated twice with
hexanes to afford 12.50 g (.about.100%) of product as a white
solid. ESI-MS m/z 331 (MH).sup.+.
Step 2. Synthesis of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
l)-benzoic acid tert-butyl ester
Phosphorous pentachloride (7.90 g, 37.9 mmol) was added in one
portion to a solution of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
l)-benzoic acid (12.50 g, 37.9 mmol) in toluene (105 mL) under
argon. The reaction was stirred until homogeneous (.about.40
minutes). The reaction mixture was poured into t-butanol (105 mL)
and stirred under argon for 18.5 h. The reaction was concentrated
in vacuo and the residue purified by flash column chromatography on
silica gel with 0-6% EtOAc/hexane to afford 9.78 g (67%) of
product. ESI-MS m/z 409 (M+Na).sup.+.
Step 3. Synthesis of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester
A solution of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
l)-benzoic acid tert-butyl ester (9.78 g, 25.3 mmol) and
chloroiodomethane (2.9 mL, 39.8 mmol) in THF (72 mL) under argon
was cooled to -100.degree. C. (MeOH, liquid N.sub.2 slush bath).
n-BuLi (15.0 mL, 2.5M in hexanes, 37.5 mmol) was added dropwise
over 25 minutes. The reaction was allowed to slowly warm to room
temperature and stirred for a total of 17.5 h. The reaction was
quenched with H.sub.2O and extracted with EtOAc (3.times.). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. Purification
by flash chromatography (0-7% EtOAc/hexane) provided 8.92 g (88%)
of product as a clear oil. ESI-MS m/z 401 (MH).sup.+.
Step 4. Synthesis of
3-[2-[2-(4-tert-Butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2-(2,9,9-
-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-
-benzoic acid tert-butyl ester
A solution of dichloromethane (DCM, 0.58 mL, 9.08 mmol) in THF (6.2
mL) under argon was cooled to -100.degree. C. (MeOH, liquid N.sub.2
slush bath). n-BuLi (3.9 mL, 2.5M in hexane, 7.80 mmol) was added
dropwise over 15 minutes and the reaction stirred at -100.degree.
C. for 30 minutes. A THF (5.7 mL) solution of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester (2.13 g, 5.33 mmol) was
added dropwise over 15 minutes. After 10 minutes, the cooling bath
was removed and the reaction stirred at 0.degree. C. for 1 h. The
reaction was then cooled to -78.degree. C. for 30 minutes. LiHMDS
(8.0 mL, 1.0M in THF, 8.0 mmol) was added dropwise over 10 minutes
and the reaction allowed to slowly warm to room temperature while
stirring overnight. Upon cooling to -10.degree. C., anhydrous MeOH
(0.28 mL, 6.92 mmol) was added and the reaction stirred at
-10.degree. C. for 1 h then warmed to room temperature for 1 h. The
reaction was cooled back down to -20.degree. C. and bromoacetyl
bromide (0.61 mL, 7.00 mmol) was added slowly. After 10 minutes,
the cooling bath was removed and the reaction stirred at room
temperature for 3.5 h. At this stage, LCMS indicated the formation
of the
3-[2-(2-Bromo-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6-
.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
intermediate.
In a separate dry round bottom flask under argon containing
4-(N-boc-amino)piperidine (1.58 g, 7.88 mmol), THF (5.0 mL) and
potassium carbonate (0.74 g, 6.23 mmol) were added. To this flask
was added the previously prepared bromide solution and the reaction
stirred at room temperature for 16 h. The reaction was quenched
with H.sub.2O and extracted with EtOAc (3.times.). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by a reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-100% AcCN:H.sub.2O (with 0.1% TFA)] to afford 0.52 g of product.
ESI-MS m/z 670 (MH).sup.+.
Step 5. Synthesis of
3-[2-(4-Amino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-benzo-
[e][1,2]oxaborinine-8-carboxylic acid
A solution of
3-[2-[2-(4-tert-Butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2-(2,9,9-
-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-
-benzoic acid tert-butyl ester (0.52 g, 0.78 mmol) in DCM (12 mL)
under argon was cooled to -78.degree. C. Boron trichloride (4.0 mL,
1.0M in DCM, 4.0 mmol) was added dropwise over 5 minutes. The
reaction was stirred at -78.degree. C. for 1 h then warmed to
0.degree. C. for 30 minutes. The reaction was quenched with
H.sub.2O (6 mL), warmed to room temperature over 15 minutes, and
concentrated in vacuo to remove DCM. The remaining aqueous layer
was extracted with diethyl ether (3.times.). The product remained
in the aqueous layer and was purified by reverse phase preparative
HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-50%
AcCN:H.sub.2O (with 0.1% TFA)] to afford 3.4 mg of product as a
white solid. ESI-MS m/z 348 (MH).sup.+.
Example 2:
2-Hydroxy-3-[2-(4-pyridin-2-yl-piperazin-1-yl)-acetylamino]-3,4-
-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00058##
Step 1. Synthesis of
2-Methoxy-3-[2-[2-(4-pyridin-2-yl-piperazin-1-yl)-acetylamino]-2-(2,9,9-t-
rimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic
acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and 1-(2-Pyridyl)piperazine
following the procedure described in Step 4 of Example 1. The crude
product was purified by a reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to give an 8% yield of product. ESI-MS m/z 633
(MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(4-pyridin-2-yl-piperazin-1-yl)-acetylamino]-3,4-dihydro-2-
H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
2-Methoxy-3-[2-[2-(4-pyridin-2-yl-piperazin-1-yl)-acetylamino]-2-(2,9,9-t-
rimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic
acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 4%
yield of product as a white solid. ESI-MS m/z 411 (MH).sup.+.
Example 3:
3-{2-[4-(2-Dimethylamino-ethyl)-piperazin-1-yl]-acetylamino}-2--
hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic
acid
##STR00059##
Step 1. Synthesis of
3-[2-{2-[4-(2-Dimethylamino-ethyl)-piperazin-1-yl]-acetylamino}-2-(2,9,9--
trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy--
benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
1-[2-(Dimethylamino)ethyl]piperazine following the procedure
described in Step 4 of Example 1. The crude product was purified by
a reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-60% AcCN:H.sub.2O (with 0.1% TFA)] to give a 2%
yield of product. ESI-MS m/z 627 (MH).sup.+.
Step 2. Synthesis of
3-{2-[4-(2-Dimethylamino-ethyl)-piperazin-1-yl]-acetylamino}-2-hydroxy-3,-
4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(2-Dimethylamino-ethyl)-piperazin-1-yl]-acetylamino}-2-(2,9,9--
trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy--
benzoic acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 7%
yield of product as a white solid. ESI-MS m/z 405 (MH).sup.+.
Example 4:
2-Hydroxy-3-(2-piperazin-1-yl-acetylamino)-3,4-dihydro-2H-benzo-
[e][1,2]oxaborinine-8-carboxylic acid
##STR00060##
Step 1. Synthesis of
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-piperazine-
-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and 1-Boc-piperazine
following the procedure described in Step 4 of Example 1. The crude
product was purified by a reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to give a 10% yield of product. ESI-MS m/z 656
(MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-(2-piperazin-1-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]ox-
aborinine-8-carboxylic acid
Prepared from
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-piperazine-
-1-carboxylic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-20% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 8% yield of product as a white solid. ESI-MS m/z 334
(MH).sup.+.
Example 5:
3-[2-(4-Aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00061##
Step 1. Synthesis of
3-[2-(2-Chloro-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[-
6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester
A solution of DCM (1.1 mL, 17.2 mmol) in THF (12 mL) under argon
was cooled to -100.degree. C. (MeOH, liquid N.sub.2 slush bath).
n-BuLi (7.1 mL, 2.5M in hexane, 17.8 mmol) was added dropwise over
15 minutes and the reaction stirred at -100.degree. C. for 30
minutes. A THF (9.0 mL) solution of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester (4.00 g, 10.0 mmol) was
added dropwise over 15 minutes. After 10 minutes, the cooling bath
was removed and the reaction stirred at 0.degree. C. for 1 h. The
reaction was then cooled to -78.degree. C. for 30 minutes. LiHMDS
(15.0 mL, 1.0M in THF, 15.0 mmol) was added dropwise over 10
minutes and the reaction allowed to slowly warm to room temperature
while stirring overnight. Upon cooling to -10.degree. C., anhydrous
MeOH (0.50 mL, 12.4 mmol) was added and the reaction stirred at
-10.degree. C. for 1 h then warmed to room temperature for 1 h. A
portion (.about.2.50 mmol) of the reaction mixture was transferred
to a separate round bottom flask under argon. Chloroacetyl chloride
(0.29 mL, 3.65 mmol) was added dropwise and the reaction was
stirred at room temperature for 3 h. The reaction was quenched with
H.sub.2O and extracted with EtOAc (3.times.). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude product was carried to the next step
without purification.
Step 2. Synthesis of
3-[2-{2-[4-(tert-Butoxycarbonylamino-methyl)-piperidin-1-yl]-acetylamino}-
-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]--
2-methoxy-benzoic acid tert-butyl ester
To a solution of
3-[2-(2-Chloro-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[-
6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
(1.26 g, 2.50 mmol) in N,N-dimethylformamide (DMF, 11.0 mL) was
added t-butyl N-(4-piperidinylmethyl)carbonate (0.550 g, 2.57
mmol), potassium carbonate (0.361 g, 3.05 mmol), and
tetrabutylammonium bromide (0.038 g, 0.118 mmol) under argon. The
reaction was stirred at room temperature for 65 h. The reaction was
quenched with H.sub.2O and extracted with EtOAc (3.times.). The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by a reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)]
to afford 0.066 g (4% over 2 steps) of product. ESI-MS m/z 684
(MH).sup.+.
Step 3. Synthesis of
3-[2-(4-Aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(tert-Butoxycarbonylamino-methyl)-piperidin-1-yl]-acetylamino}-
-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]--
2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 11% yield of product as a white solid. ESI-MS m/z 362
(MH).sup.+.
Example 6:
3-[2-(R-3-Amino-pyrrolidin-1-yl)-acetylamino]-2-hydroxy-3,4-dih-
ydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00062##
Step 1. Synthesis of
3-[2-[2-(3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methox-
y-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(R)-3-N-Boc-aminopyrrolidine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 24%
yield of product. ESI-MS m/z 656 (MH).
Step 2. Synthesis of
3-[2-(R-3-Amino-pyrrolidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-be-
nzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methox-
y-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 5% yield of product as a white solid. ESI-MS m/z 334
(MH).sup.+.
Example 7:
3-[2-(S-3-Amino-pyrrolidin-1-yl)-acetylamino]-2-hydroxy-3,4-dih-
ydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00063##
Step 1. Synthesis of
3-[2-[2-(3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methox-
y-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(S)-3-N-Boc-aminopyrrolidine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 28%
yield of product. ESI-MS m/z 656 (MH).sup.+.
Step 2. Synthesis of
3-[2-(S-3-Amino-pyrrolidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-be-
nzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methox-
y-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 29% yield of product as a white solid. ESI-MS m/z 334
(MH).sup.+.
Example 8:
2-Hydroxy-3-[2-(2-oxo-piperazin-1-yl)-acetylamino]-3,4-dihydro--
2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00064##
Step 1. Synthesis of
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-3-oxo-pipe-
razine-1-carboxylic acid tert-butyl ester
A solution of dichloromethane (0.58 mL, 9.08 mmol) in THF (6.2 mL)
under argon was cooled to -100.degree. C. (MeOH, liquid N.sub.2
slush bath). n-BuLi (3.9 mL, 2.5M in hexane, 7.80 mmol) was added
dropwise over 15 minutes and the reaction stirred at -100.degree.
C. for 30 minutes. A THF (5.7 mL) solution of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester (2.13 g, 5.33 mmol) was
added dropwise over 15 minutes. After 10 minutes, the cooling bath
was removed and the reaction stirred at 0.degree. C. for 1 h. The
reaction was then cooled to -78.degree. C. for 30 minutes. LiHMDS
(8.0 mL, 1.0M in THF, 8.0 mmol) was added dropwise over 10 minutes
and the reaction allowed to slowly warm to room temperature while
stirring overnight. Upon cooling to -10.degree. C., anhydrous MeOH
(0.28 mL, 6.92 mmol) was added and the reaction stirred at
-10.degree. C. for 1 h then warmed to room temperature for 1 h.
To a separate dry round bottom flask under argon containing
4-N-Boc-2-oxo-piperazine-1-acetic acid (0.318 g, 1.23 mmol) and DCM
(3.4 mL) was added N-methylmorpholine (0.20 mL, 1.82 mmol) and HATU
(0.494 g, 1.70 mmol). DMF (1.6 mL) was added to make the reaction
homogeneous. The reaction was stirred at room temperature for 3 h.
A portion of the solution (-2.44 mmol) prepared above was added
slowly at 0.degree. C. and the reaction was gradually warmed to
room temperature and stirred for 44 h. The reaction was quenched
with H.sub.2O and extracted with EtOAc (3.times.). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by a reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-100% AcCN:H.sub.2O (with 0.1% TFA)] to afford 0.158 g (19%) of
product. ESI-MS m/z 670 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(2-oxo-piperazin-1-yl)-acetylamino]-3,4-dihydro-2H-benzo[e-
][1,2]oxaborinine-8-carboxylic acid
Prepared from
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-3-oxo-pipe-
razine-1-carboxylic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)]
to give a 13% yield of product as a white solid. ESI-MS m/z 348
(MH).sup.+.
Example 9:
2-Hydroxy-3-[2-(pyrrolidin-3-ylamino)-acetylamino]-3,4-dihydro--
2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00065##
Step 1. Synthesis of
3-({[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-amino)-py-
rrolidine-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(R)-(+)-1-Boc-3-aminopyrrolidine following the procedure described
in Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 9%
yield of product. ESI-MS m/z 656 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(pyrrolidin-3-ylamino)-acetylamino]-3,4-dihydro-2H-benzo[e-
][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-({[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-amino)-py-
rrolidine-1-carboxylic acid tert-butyl ester and BCl.sub.3
following the procedure described in Step 5 of Example 1. The crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-30% AcCN:H.sub.2O (with
0.1% TFA)] to give a 6% yield of product as a white solid. ESI-MS
m/z 334 (MH).sup.+.
Example 10:
3-[2-(R-3-Amino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid
##STR00066##
Step 1. Synthesis of
3-[2-[2-(3-tert-Butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2-(2,9,9-
-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-
-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(R)-3-(Boc-amino)piperidine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 10%
yield of product. ESI-MS m/z 670 (MH).sup.+.
Step 2. Synthesis of
3-[2-(R-3-Amino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
-[2-[2-(3-tert-Butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2-(2,9,9--
trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy--
benzoic acid tert-butyl ester ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 10% yield of product as a white solid. ESI-MS m/z 348
(MH).sup.+.
Example 11:
3-[2-(S-3-Amino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid
##STR00067##
Step 1. Synthesis of
3-[2-[2-(3-tert-Butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2-(2,9,9-
-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-
-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(S)-3-(Boc-amino)piperidine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 10%
yield of product. ESI-MS m/z 670 (MH).sup.+.
Step 2. Synthesis of
3-[2-(S-3-Amino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
-[2-[2-(3-tert-Butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2-(2,9,9--
trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy--
benzoic acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 6%
yield of product as a white solid.
ESI-MS m/z 348 (MH).sup.+.
Example 12:
2-Hydroxy-3-[2-(4-Hydroxy-piperidin-1-yl)-acetylamino]-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid
##STR00068##
Step 1. Synthesis of
3-[2-[2-(4-Hydroxy-piperidin-1-yl)-acetylamino]-2-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic
acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and 4-hydroxypiperidine
following the procedure described in Step 4 of Example 1. The crude
product was purified by a reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to give a 15% yield of product. ESI-MS m/z 571
(MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(4-hydroxy-piperidin-1-yl)-acetylamino]-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(4-Hydroxy-piperidin-1-yl)-acetylamino]-2-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic
acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 4%
yield of product as a white solid. ESI-MS m/z 349 (MH).sup.+.
Example 13:
3-(2-[1,4]Diazepan-1-yl-acetylamino)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,-
2]oxaborinine-8-carboxylic acid
##STR00069##
Step 1. Synthesis of
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-[1,4]diaze-
pane-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and 1-Boc-homopiperazine
following the procedure described in Step 4 of Example 1. The crude
product was purified by a reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to give a 13% yield of product. ESI-MS m/z 670
(MH).sup.+.
Step 2. Synthesis of
3-(2-[1,4]Diazepan-1-yl-acetylamino)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,-
2]oxaborinine-8-carboxylic acid
Prepared from
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-[1,4]diaze-
pane-1-carboxylic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 9% yield of product as a white solid. ESI-MS m/z 348
(MH).sup.+.
Example 14:
2-Hydroxy-3-[2-(4-methylamino-piperidin-1-yl)-acetylamino]-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00070##
Step 1. Synthesis of
3-[2-{2-[4-(tert-Butoxycarbonyl-methyl-amino)-piperidin-1-yl]-acetylamino-
}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricylo[6.1.1.02,6]dec-4-yl)-ethyl]--
2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
4-N-Boc-4-N-methylaminopiperidine following the procedure described
in Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 14%
yield of product. ESI-MS m/z 684 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(4-methylamino-piperidin-1-yl)-acetylamino]-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(tert-Butoxycarbonyl-methyl-amino)-piperidin-1-yl]-acetylamino-
}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)]
to give a 23% yield of product as a white solid. ESI-MS m/z 362
(MH).sup.+.
Example 15:
2-Hydroxy-3-[2-(4-thiazol-2-yl-piperazin-1-yl)-acetylamino]-3,4-dihydro-2-
H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00071##
Step 1. Synthesis of
2-Methoxy-3-[2-[2-(4-thiazol-2-yl-piperazin-1-yl)-acetylamino]-2-(2,9,9-t-
rimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic
acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
1-thiazole-2-yl-piperazine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 24%
yield of product. ESI-MS m/z 639 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(4-thiazol-2-yl-piperazin-1-yl)-acetylamino]-3,4-dihydro-2-
H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
2-Methoxy-3-[2-[2-(4-thiazol-2-yl-piperazin-1-yl)-acetylamino]-2-(2,9,9-t-
rimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic
acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 25%
yield of product as a white solid. ESI-MS m/z 417 (MH).sup.+.
Example 16:
3-{2-[4-(2-Amino-ethyl)-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00072##
Step 1. Synthesis of
3-[2-{2-[4-(2-tert-Butoxycarbonylamino-ethyl)-piperazin-1-yl]-acetylamino-
}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
1-(2-N-Boc-aminoethyl)piperazine following the procedure described
in Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 18%
yield of product. ESI-MS m/z 699 (MH).sup.+.
Step 2. Synthesis of
3-{2-[4-(2-Amino-ethyl)-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(2-tert-Butoxycarbonylamino-ethyl)-piperazin-1-yl]-acetylamino-
}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)]
to give a 7% yield of product as a white solid. ESI-MS m/z 377
(MH).sup.+.
Example 17:
3-{2-[4-(2-Amino-acetyl)-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4-dihyd-
ro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00073##
Step 1. Synthesis of
3-[2-{2-[4-(2-tert-Butoxycarbonylamino-acetyl)-piperazin-1-yl]-acetylamin-
o}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricylo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(2-oxo-2-piperazin-1-yl-ethyl)carbamic acid t-butylester following
the procedure described in Step 4 of Example 1. The crude product
was purified by a reverse phase preparative HPLC [Waters Sunfire
C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1%
TFA)] to give a 15% yield of product. ESI-MS m/z 713
(MH).sup.+.
Step 2. Synthesis of
3-{2-[4-(2-Amino-acetyl)-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4-dihyd-
ro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(2-tert-Butoxycarbonylamino-acetyl)-piperazin-1-yl]-acetylamin-
o}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl-
]-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)]
to give a 14% yield of product as a white solid. ESI-MS m/z 391
(MH).sup.+.
Example 18:
2-Hydroxy-3-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-acetylamino}-3,4-dihy-
dro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00074##
Step 1. Synthesis of
3-[2-{2-[4-(2-Benzyloxy-ethyl)-piperazin-1-yl]-acetylamino}-2-(2,9,9-trim-
ethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benz-
oic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
1-(2-benzyloxyethyl)piperazine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 9%
yield of product. ESI-MS m/z 690 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-acetylamino}-3,4-dihy-
dro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(2-Benzyloxy-ethyl)-piperazin-1-yl]-acetylamino}-2-(2,9,9-trim-
ethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benz-
oic acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-40% AcCN:H.sub.2O (with 0.1% TFA)] to give a 8%
yield of product as a white solid.
ESI-MS m/z 378 (MH).
Example 19:
3-[2-(3-Aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-
-benzoe[e][1,2]oxaborinine-8-carboxylic acid
##STR00075##
Step 1. Synthesis of
3-[2-{2-[3-(tert-Butoxycarbonylamino-methyl)-piperidin-1-yl]-acetylamino}-
-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]--
2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
3-(Boc-aminomethyl)piperidine following the procedure described in
Step 4 of Example 1. The crude product was purified by a reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 15%
yield of product. ESI-MS m/z 684 (MH).sup.+.
Step 2. Synthesis of
3-[2-(3-Aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[3-(tert-Butoxycarbonylamino-methyl)-piperidin-1-yl]-acetylamino}-
-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]--
2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-40% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 28% yield of product as a white solid. ESI-MS m/z 362
(MH).sup.+.
Example 20:
2-Hydroxy-3-[2-(3-hydroxy-4-methylamino-piperidin-1-yl)-acetylamino]-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00076##
Step 1. Synthesis of 3,6-Dihydro-2H-pyridine-1-carboxylic acid
benzyl ester
Triethylamine (16.8 mL, 120.5 mmol) was added to a solution of
1,2,3,6-tetrahydropyridine (5.5 mL, 60.3 mmol) in DCM (50 mL) under
argon. The solution was cooled to 0.degree. C. for 15 minutes.
Benzyl chloroformate (9.5 mL, 66.5 mmol) was added slowly. The
reaction was stirred at 0.degree. C. for 30 minutes then allowed to
come to room temperature overnight. The reaction was diluted with
diethyl ether (300 mL) and washed successively with 0.5N HCl
(2.times.), saturated NaHCO.sub.3, and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
afford 8.58 g (65%) of product as a clear oil. ESI-MS m/z 218
(MH).sup.+.
Step 2. Synthesis of 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic
acid benzyl ester
A solution of 3,6-Dihydro-2H-pyridine-1-carboxylic acid benzyl
ester (8.58 g, 39.5 mmol) in DCM (80 mL) under argon was cooled to
0.degree. C. m-Chloroperoxybenzoic acid (10.95 g, 75%, 47.6 mmol)
in DCM (60 mL) was added dropwise over 20 minutes. The reaction was
stirred at 0.degree. C. for 30 minutes then allowed to come to room
temperature overnight. The reaction was diluted with DCM and washed
successively with aqueous Na.sub.2S.sub.2O.sub.3, saturated
NaHCO.sub.3, and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide 8.45 g
(92%) of a white solid. ESI-MS m/z 256 (M+Na).sup.+.
Step 3. Synthesis of 4-Azido-3-hydroxy-piperidine-1-carboxylic acid
benzyl ester and 3-Azido-4-hydroxy-piperidine-1-carboxylic acid
benzyl ester
Sodium azide (3.56 g, 54.8 mmol) in acetone (50 mL)/H.sub.2O (25
mL) was added slowly to a solution of
7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester
(8.45 g, 36.2 mmol) in DMF (72 mL). The reaction was heated at
80.degree. C. for 24 h. The reaction was cooled to room temperature
and concentrated in vacuo. The residue was diluted with ethyl
acetate and washed with H.sub.2O, 10% aqueous LiCl, and brine. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification by flash chromatography (0-50%
EtOAc/hexane) afforded 6.51 g of
4-Azido-3-hydroxy-piperidine-1-carboxylic acid benzyl ester and
1.12 g of 3-Azido-4-hydroxy-piperidine-1-carboxylic acid benzyl
ester for a total 76% yield. ESI-MS m/z 299 (M+Na).sup.+.
Step 4. Synthesis of
4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid
benzyl ester
A solution of 4-Azido-3-hydroxy-piperidine-1-carboxylic acid benzyl
ester (6.51 g, 23.6 mmol), triphenylphosphine (12.52 g, 47.7 mmol),
H.sub.2O (1.8 mL, 100 mmol), and THF (180 mL) was heated at
70.degree. C. for 17 h. The reaction was cooled to room
temperature, diluted with ethyl acetate, and washed with IN HCl
(2.times.). The combined aqueous layers were basified to
pH.about.12 with 10 ON NaOH and extracted with ethyl acetate
(3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The product was
dissolved in DCM (130 mL) under argon. Triethylamine (4.0 mL, 28.7
mmol) and di-tert-butyldicarbonate (5.70 g, 26.1 mmol) in DCM (30
mL) were added and the reaction stirred at room temperature for 18
h. The reaction was quenched with saturated NaHCO.sub.3 and
extracted with DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Flash chromatography
(0-60% EtOAc/hexane) provided 6.48 g (78%) of product as a white
solid. ESI-MS m/z 351 (MH).sup.+.
Step 5. Synthesis of
4-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-piperidine--
1-carboxylic acid benzyl ester
A mixture of
4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid
benzyl ester (0.725 g, 2.07 mmol), imidazole (0.360 g, 5.29 mmol),
and DMF (6.0 mL) under argon was cooled to 0.degree. C. for 15
minutes. tert-Butyldimethylsilyl chloride (0.382 g, 2.53 mmol) was
added in one portion and the reaction was warmed to room
temperature for 15 h. The reaction was quenched with brine and
extracted with diethyl ether (2.times.). The combined organic
layers were dried over MgSO.sub.4, filtered, and concentrated to
afford 1.08 g of crude product which was carried to the next step
without purification. ESI-MS m/z 465 (MH).sup.+.
Step 6. Synthesis of
4-(tert-Butoxycarbonyl-methyl-amino)-3-(tert-butyl-dimethyl-silanyloxy)-p-
iperidine-1-carboxylic acid benzyl ester
A solution of
4-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-piperidine--
1-carboxylic acid benzyl ester (0.961 g, 2.07 mmol) in DMF (15 mL)
under argon was cooled to 0.degree. C. Sodium hydride (0.206 g, 60%
in mineral oil, 5.15 mmol) was added in one portion and the
reaction stirred at 0.degree. C. for 35 minutes. Iodomethane (0.32
mL, 5.14 mmol) was added dropwise and the reaction warmed to room
temperature for 22 h. The reaction was quenched with H.sub.2O and
extracted with diethyl ether (2.times.). The combined organic
layers were dried over MgSO.sub.4, filtered, and concentrated to
give 1.01 g of crude product which was carried to the next step
without purification. ESI-MS m/z 479 (MH).sup.+.
Step 7. Synthesis of
[3-(tert-Butyl-dimethyl-silanyloxy)-piperidin-4-yl]-methyl-carbamic
acid tert-butyl ester
A solution of
4-(tert-Butoxycarbonyl-methyl-amino)-3-(tert-butyl-dimethyl-silanyloxy)-p-
iperidine-1-carboxylic acid benzyl ester (0.990 g, 2.07 mmol) in
methanol (20 mL) was purged with argon for 5 minutes. Pd(OH).sub.2
(0.080 g, 20% on carbon) was added, the flask evacuated, and the
reaction placed under a hydrogen atmosphere for 24 h. The reaction
was filtered through a Celite-plugged filter frit, washed with
methanol and DCM, and concentrated in vacuo to afford 0.750 g of
crude product as a white solid. ESI-MS m/z 345 (MH).sup.+.
Step 8. Synthesis of
3-[2-{2-[4-(tert-Butoxycarbonyl-methyl-amino)-3-(tert-butyl-dimethyl-sila-
nyloxy)-piperidin-1-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-t-
ricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid
tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
[3-(tert-Butyl-dimethyl-silanyloxy)-piperidin-4-yl]-methyl-carbamic
acid tert-butyl ester following the procedure described in Step 4
of Example 1.
The crude product was purified by a reverse phase preparative HPLC
[Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100%
AcCN:H.sub.2O (with 0.1% TFA)] to give a 6% yield of product.
ESI-MS m/z 814 (MH).sup.+.
Step 9. Synthesis of
2-Hydroxy-3-[2-(3-hydroxy-4-methylamino-piperidin-1-yl)-acetylamino]-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(tert-Butoxycarbonyl-methyl-amino)-3-(tert-butyl-dimethyl-sila-
nyloxy)-piperidin-1-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-t-
ricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid
tert-butyl ester and BCl.sub.3 following the procedure described in
Step 5 of Example 1. The crude product was purified by reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 5%
yield of product as a white solid. ESI-MS m/z 378 (MH).sup.+.
Example 21:
3-[2-(4-Amino-3-methoxy-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00077##
Step 1. Synthesis of
4-tert-Butoxycarbonylamino-3-methoxy-piperidine-1-carboxylic acid
benzyl ester
A solution of
4-tert-Butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid
benzyl ester (prepared in Example 20, Step 4, 0.840 g, 2.40 mmol)
in THF (6.0 mL) under argon was cooled to 0.degree. C. Sodium
hydride (0.123 g, 60%, 3.08 mmol) was added in one portion and the
reaction stirred at 0.degree. C. for 30 minutes. Iodomethane (0.16
mL, 2.57 mmol) was added slowly and the reaction warmed to room
temperature for 17 h. The reaction was quenched with H.sub.2O and
extracted with ethyl acetate (2.times.). The combined organic
layers were washed with saturated NaHCO.sub.3 and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide 0.840 g
(96%) of product. ESI-MS m/z 365 (MH).sup.+.
Step 2. Synthesis of (3-Methoxy-piperidin-4-yl)-carbamic acid
tert-butyl ester
A solution of
4-tert-Butoxycarbonylamino-3-methoxy-piperidine-1-carboxylic acid
benzyl ester (0.840 g, 2.31 mmol) in methanol (24 mL) was purged
with argon for 5 minutes. Pd(OH).sub.2 (0.067, 20% on carbon) was
added, flask evacuated, and the reaction stirred under hydrogen
atmosphere for 24 h. The reaction was filtered through a
Celite-plugged filter frit, washed with methanol and DCM, and
concentrated to afford 0.490 g (92%) of product as a white solid.
ESI-MS m/z 365 (MH).sup.+.
Step 3. Synthesis of
3-[2-{2-[4-(tert-Butoxycarbonyl-methyl-amino)-3-methoxy-piperidin-1-yl]-a-
cetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4--
yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(3-Methoxy-piperidin-4-yl)-carbamic acid tert-butyl ester following
the procedure described in Step 4 of Example 1. The crude product
was purified by a reverse phase preparative HPLC [Waters Sunfire
C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1%
TFA)] to give a 11% yield of product. ESI-MS m/z 700
(MH).sup.+.
Step 4. Synthesis of
3-[2-(4-Amino-3-methoxy-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(tert-Butoxycarbonyl-methyl-amino)-3-methoxy-piperidin-1-yl]-a-
cetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4--
yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3
following the procedure described in Step 5 of Example 1. The crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-40% AcCN:H.sub.2O (with
0.1% TFA)] to give a 3% yield of product as a white solid. ESI-MS
m/z 378 (MH).sup.+.
Example 22:
3-[3-(4-Amino-piperidin-1-yl)-propionylamino]-2-hydroxy-3,4-dihydro-2H-be-
nzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00078##
Step 1. Synthesis of
3-[2-[3-(4-tert-Butoxycarbonylamino-piperidin-1-yl)-propionylamino]-2-(2,-
9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-meth-
oxy-benzoic acid tert-butyl ester
A solution of dichloromethane (0.31 mL, 4.85 mmol) in THF (3.4 mL)
under argon was cooled to -100.degree. C. (MeOH, liquid N.sub.2
slush bath). n-BuLi (1.7 mL, 2.5M in hexane, 4.25 mmol) was added
dropwise over 10 minutes and the reaction stirred at -100.degree.
C. for 30 minutes. A THF (3.0 mL) solution of
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester (1.14 g, 2.85 mmol) was
added dropwise over 12 minutes. After 10 minutes, the cooling bath
was removed and the reaction stirred at 0.degree. C. for 1 h. The
reaction was then cooled to -78.degree. C. for 30 minutes. LiHMDS
(4.4 mL, 1.0M in THF, 4.4 mmol) was added dropwise over 10 minutes
and the reaction allowed to slowly warm to room temperature while
stirring overnight. Upon cooling to -10.degree. C., anhydrous MeOH
(0.16 mL, 3.96 mmol) was added and the reaction stirred at
-10.degree. C. for 1 h then warmed to room temperature for 1 h. The
reaction was cooled back down to -20.degree. C. and
3-bromopropionyl chloride (0.37 mL, 3.67 mmol) was added slowly.
After 10 minutes, the cooling bath was removed and the reaction
stirred at room temperature for 4.5 h. At this stage, LCMS
indicated the formation of the
3-[2-(3-Bromo-propionylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricycl-
o[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester intermediate.
In a separate dry round bottom flask under argon,
4-(N-Boc-amino)piperidine (0.715 g, 3.57 mmol) and THF (2.6 mL)
were added. Sodium hydride (0.177 g, 60%, 4.42 mmol) was added
followed by the previously prepared bromide solution and the
reaction stirred at room temperature for 17 h. The reaction was
quenched with H.sub.2O and extracted with EtOAc (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by a reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-100% AcCN:H.sub.2O (with 0.1% TFA)] to afford 0.112 g (11%) of
product. ESI-MS m/z 684 (MH).sup.+.
Step 2. Synthesis of
3-[3-(4-Amino-piperidin-1-yl)-propionylamino]-2-hydroxy-3,4-dihydro-2H-be-
nzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[3-(4-tert-Butoxycarbonylamino-piperidin-1-yl)-propionylamino]-2-(2,-
9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-meth-
oxy-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 42% yield of product as a white solid.
ESI-MS m/z 362 (MH).sup.+.
Example 23:
2-Hydroxy-3-(3-piperazin-1-yl-propionylamino)-3,4-dihydro-2H-benzo[e][1,2-
]oxaborinine-8-carboxylic acid
##STR00079##
Step 1. Synthesis of
4-{2-[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-d-
ioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-ethyl}-piperazin-
e-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and 1-Z-piperazine following
the procedure described in Step 1 of Example 22. The crude product
was purified by a reverse phase preparative HPLC [Waters Sunfire
C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1%
TFA)] to give a 9% yield of product. ESI-MS m/z 704 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-(3-piperazin-1-yl-propionylamino)-3,4-dihydro-2H-benzo[e][1,2-
]oxaborinine-8-carboxylic acid
Prepared from
4-{2-[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-d-
ioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-ethyl}-piperazin-
e-1-carboxylic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 m, 19.times.50 mm, 5-95% AcCN:H.sub.2O (with 0.1% TFA)] to give a
35% yield of product as a white solid. ESI-MS m/z 348
(MH).sup.+.
Example 24:
3-[2-(4-Amino-3-hydroxy-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00080##
Step 1. Synthesis of
[3-(tert-Butyl-dimethyl-silanyloxy)-piperidin-4-yl]-carbamic acid
tert-butyl ester
A solution of
4-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-piperidine--
1-carboxylic acid benzyl ester (0.907 g, 1.95 mmol) in methanol (22
mL) was purged with argon for 5 minutes. Pd(OH).sub.2 (0.073 g, 20%
on carbon) was added, the flask evacuated, and the reaction placed
under a hydrogen atmosphere for 22 h. The reaction was filtered
through a Celite-plugged filter frit, washed with methanol and DCM,
and concentrated in vacuo to afford 0.656 g of crude product as a
white solid. ESI-MS m/z 331 (MH).sup.+.
Step 2. Synthesis of
3-[2-{2-[4-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-pi-
peridin-1-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.-
1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester
Preparation of the
3-[2-(2-Bromo-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6-
.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
intermediate was carried out as in Step 4 of Example 1.
In a separate dry round bottom flask under argon,
[3-(tert-Butyl-dimethyl-silanyloxy)-piperidin-4-yl]-carbamic acid
tert-butyl ester (0.656 g, 1.98 mmol) and THF (2.6 mL) were added.
Sodium hydride (0.098 g, 60%, 2.45 mmol) was added followed by the
previously prepared bromide solution and the reaction stirred at
room temperature for 17 h. The reaction was quenched with H.sub.2O
and extracted with EtOAc (3.times.). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by a reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to afford 0.084 g (8%) of product. ESI-MS m/z 801
(MH).sup.+.
Step 3. Synthesis of
3-[2-(4-Amino-3-hydroxy-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-tert-Butoxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-pi-
peridin-1-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.-
1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
and BCl.sub.3 following the procedure described in Step 5 of
Example 1. The crude product was purified by reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-50% AcCN:H.sub.2O (with 0.1% TFA)] to give a 4% yield of product
as a white solid. ESI-MS m/z 364 (MH).sup.+.
Example 25:
3-[2-(4-Carboxymethyl-piperazin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro--
2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00081##
Step 1. Synthesis of
3-[2-[2-(4-tert-Butoxycarbonylmethyl-piperazin-1-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methox-
y-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
tert-butylpiperazin-1-ylacetate following the procedure described
in Step 2 of Example 24. The crude product was purified by a
reverse phase preparative HPLC [Phenomenex Luna, 5 .mu.m,
30.times.75 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 8%
yield of product. ESI-MS m/z 670 (MH).sup.+.
Step 2. Synthesis of
3-[2-(4-Carboxymethyl-piperazin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro--
2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(4-tert-Butoxycarbonylmethyl-piperazin-1-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methox-
y-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 12% yield of product as a white solid.
ESI-MS m/z 392 (MH).sup.+.
Example 26:
3-[2-(3-Amino-4-hydroxy-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00082##
Step 1. Synthesis of
3-tert-Butoxycarbonylamino-4-hydroxy-piperidine-1-carboxylic acid
benzyl ester
A solution of 3-Azido-4-hydroxy-piperidine-1-carboxylic acid benzyl
ester (prepared in Step 3, Example 20) (1.12 g, 4.05 mmol),
triphenylphosphine (2.12 g, 8.10 mmol), H.sub.2O (0.40 mL, 22.2
mmol), and THF (31 mL) was heated at 70.degree. C. for 17 h. The
reaction was cooled to room temperature, diluted with ethyl
acetate, and washed with IN HCl (2.times.). The combined aqueous
layers were basified to pH.about.12 with 10N NaOH and extracted
with ethyl acetate (3.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
product was dissolved in DCM (22 mL) under argon. Triethylamine
(0.70 mL, 5.02 mmol) and di-tert-butyldicarbonate (0.991 g, 4.54
mmol) in DCM (8 mL) were added and the reaction stirred at room
temperature for 18 h. The reaction was quenched with saturated
NaHCO.sub.3 and extracted with DCM. The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Flash
chromatography (0-100% EtOAc/hexane) provided 1.08 g (76%) of
product as a white solid.
ESI-MS m/z 351 (MH).
Step 2. Synthesis of (4-Hydroxy-piperidin-3-yl)-carbamic acid
tert-butyl ester
A solution of
3-tert-Butoxycarbonylamino-4-hydroxy-piperidine-1-carboxylic acid
benzyl ester (1.08 g, 3.08 mmol) in methanol (32 mL) was purged
with argon for 10 minutes. Pd(OH).sub.2 (0.086 g, 20% on carbon)
was added, the flask evacuated, and the reaction placed under a
hydrogen atmosphere for 23 h. The reaction was filtered through a
Celite-plugged filter frit, washed with methanol and DCM, and
concentrated in vacuo to afford 0.676 g of crude product as a white
solid. ESI-MS m/z 217 (MH).sup.+.
Step 3. Synthesis of
3-[2-[2-(3-tert-Butoxycarbonylamino-4-hydroxy-piperidin-1-yl)-acetylamino-
]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(4-Hydroxy-piperidin-3-yl)-carbamic acid tert-butyl ester following
the procedure described in Step 2 of Example 24. The crude product
was purified by a reverse phase preparative HPLC [Phenomenex Luna,
5 .mu.m, 30.times.75 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 3% yield of product. ESI-MS m/z 686 (MH).sup.+.
Step 4. Synthesis of
3-[2-(3-Amino-4-hydroxy-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(3-tert-Butoxycarbonylamino-4-hydroxy-piperidin-1-yl)-acetylamino-
]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-40% AcCN:H.sub.2O (with 0.1% TFA)]
to give a 34% yield of product as a white solid. ESI-MS m/z 364
(MH).sup.+.
Example 27:
3-{2-[4-(3-Amino-propionylamino)-piperidin-1-yl]-acetylamino}-2-hydroxy-3-
,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00083##
Step 1. Synthesis of
4-(3-tert-Butoxycarbonylamino-propionylamino)-piperidine-1-carboxylic
acid benzyl ester
N-Methylmorpholine (0.44 mL, 4.00 mmol) and HATU (1.05 g, 2.76
mmol) were added to a solution of Boc-.beta.-Ala-OH (0.501 g, 2.65
mmol) in DCM (24 mL) under argon and the reaction was stirred at
room temperature for 30 minutes. 4-Amino-1-N-CBz-piperidine (0.588
g, 2.51 mmol) was added in one portion and the reaction stirred for
95 h. The reaction was quenched with 0.25M HCl and extracted with
DCM. The organic layer was washed with saturated NaHCO.sub.3 and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
provide 1.00 g of crude product which was carried to the next step
without purification. ESI-MS m/z 406 (MH).sup.+.
Step 2. Synthesis of [2-(Piperidin-4-ylcarbamoyl)-ethyl]-carbamic
acid tert-butyl ester
A solution of
4-(3-tert-Butoxycarbonylamino-propionylamino)-piperidine-1-carboxylic
acid benzyl ester (1.00 g, 2.47 mmol) in methanol (25 mL) was
purged with argon for 8 minutes. Pd(OH).sub.2 (0.088 g, 20% on
carbon) was added, the flask evacuated, and the reaction placed
under a hydrogen atmosphere for 23 h. The reaction was filtered
through a Celite-plugged filter frit, washed with methanol and DCM,
and concentrated in vacuo to afford 0.699 g of crude product as a
white solid. ESI-MS m/z 272 (MH).sup.+.
Step 3. Synthesis of
3-[2-{2-[4-(3-tert-Butoxycarbonylamino-propionylamino)-piperidin-1-yl]-ac-
etylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
l)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
[2-(Piperidin-4-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester
following the procedure described in Step 2 of Example 24. The
crude product was purified by a reverse phase preparative HPLC
[Phenomenex Luna, 5 .mu.m, 30.times.75 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to give a 9% yield of product. ESI-MS m/z 741
(MH).sup.+.
Step 4. Synthesis of
3-{2-[4-(3-Amino-propionylamino)-piperidin-1-yl]-acetylamino}-2-hydroxy-3-
,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(3-tert-Butoxycarbonylamino-propionylamino)-piperidin-1-yl]-ac-
etylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
l)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3
following the procedure described in Step 5 of Example 1. The crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with
0.1% TFA)] to give a 29% yield of product as a white solid. ESI-MS
m/z 419 (MH).sup.+.
Example 28:
3-[2-(3,4-Diamino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-b-
enzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00084##
Step 1. Synthesis of 3,4-Dihydroxy-piperidine-1-carboxylic acid
benzyl ester
To a mixture of AD-mix-.alpha. (5.02 g), t-butanol (60 mL), and
H.sub.2O (60 mL) was added 3,6-Dihydro-2H-pyridine-1-carboxylic
acid benzyl ester (prepared in Step 1, Example 20) (2.08 g, 9.57
mmol) in t-butanol/H.sub.2O (10 mL/10 mL). The reaction was stirred
at room temperature for 42 h. Additional AD-mix-.alpha. (1.50 g)
was added and the reaction was stirred for an additional 24 h.
Sodium sulfite (2.08 g) was added and the reaction stirred for 4 h.
The reaction was diluted with saturated NaHCO.sub.3 and extracted
with DCM (2.times.). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. Flash chromatography (0-100% EtOAc/hexane followed by 10%
CH.sub.3OH/DCM) afforded 1.51 g (63%) of product. ESI-MS m/z 252
(MH).sup.+.
Step 2. Synthesis of
3,4-Bis-methanesulfonyloxy-piperidine-1-carboxylic acid benzyl
ester
A solution of 3,4-Dihydroxy-piperidine-1-carboxylic acid benzyl
ester (1.51 g, 6.01 mmol) in DCM (30 mL) under argon was cooled to
0.degree. C. Pyridine (2.5 mL, 30.9 mmol) was added followed by
slow addition of methanesulfonyl chloride (1.2 mL, 15.5 mmol). The
reaction was warmed to room temperature and stirred overnight. The
reaction was diluted with DCM and washed with IN HCl, saturated
NaHCO.sub.3, and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Flash chromatography
(0-20% CH.sub.3OH/DCM) afforded 1.62 g (66%) of product. ESI-MS m/z
252 (MH).sup.+.
Step 3. Synthesis of 3,4-Diazido-piperidine-1-carboxylic acid
benzyl ester
Sodium azide (2.58 g, 39.8 mmol) was added to a solution of
3,4-Bis-methanesulfonyloxy-piperidine-1-carboxylic acid benzyl
ester (1.62 g, 3.98 mmol) in DMF (100 mL) under argon and the
reaction was heated at 120.degree. C. for 24 h. The reaction was
cooled to room temperature and poured into ice cold H.sub.2O and
extracted with ethyl acetate (2.times.). The combined organic
layers were washed with H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to provide 1.03 g of
crude product which was carried to the next step without
purification. ESI-MS m/z 324 (M+Na).sup.+.
Step 4. Synthesis of
3,4-Bis-tert-butoxycarbonylamino-piperidine-1-carboxylic acid
benzyl ester
A solution of 3,4-Diazido-piperidine-1-carboxylic acid benzyl ester
(1.03 g, 3.42 mmol), triphenylphosphine (3.60 g, 13.7 mmol),
H.sub.2O (0.6 mL, 33.3 mmol), and THF (35 mL) was heated at
70.degree. C. for 20 h. The reaction was cooled to room
temperature, diluted with ethyl acetate, and washed with IN HCl
(2.times.). The combined aqueous layers were basified to pH-13 with
1 ON NaOH and extracted with ethyl acetate (3.times.). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The product was dissolved in DCM (15 mL) under argon.
Triethylamine (1.1 mL, 7.89 mmol) and di-tert-butyldicarbonate
(1.65 g, 7.54 mmol) in DCM (5 mL) were added and the reaction
stirred at room temperature for 65 h. The reaction was quenched
with saturated NaHCO.sub.3 and extracted with DCM. The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Flash chromatography (0-50% EtOAc/hexane) provided 0.414 g (27%) of
product as a white solid. ESI-MS m/z 450 (MH).sup.+.
Step 5. Synthesis of
(4-tert-Butoxycarbonylamino-piperidin-3-yl)-carbamic acid
tert-butyl ester
A solution of
3,4-Bis-tert-butoxycarbonylamino-piperidine-1-carboxylic acid
benzyl ester (0.414 g, 0.921 mmol) in methanol (9.0 mL) was purged
with argon for 5 minutes. Pd(OH).sub.2 (0.043 g, 20% on carbon) was
added, the flask evacuated, and the reaction placed under a
hydrogen atmosphere for 43 h. The reaction was filtered through a
Celite-plugged filter frit, washed with methanol and DCM, and
concentrated in vacuo to afford 0.286 g of crude product as a white
solid. ESI-MS m/z 316 (MH).sup.+.
Step 6. Synthesis of
3-[2-[2-(3,4-Bis-tert-butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2--
(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-m-
ethoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(4-tert-Butoxycarbonylamino-piperidin-3-yl)-carbamic acid
tert-butyl ester following the procedure described in Step 2 of
Example 24. The crude product was purified by a reverse phase
preparative HPLC [Phenomenex Luna, 5 .mu.m, 30.times.75 mm, 5-100%
AcCN:H.sub.2O (with 0.1% TFA)] to give a 10% yield of product.
ESI-MS m/z 785 (MH).sup.+.
Step 7. Synthesis of
3-[2-(3,4-Diamino-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-b-
enzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(3,4-Bis-tert-butoxycarbonylamino-piperidin-1-yl)-acetylamino]-2--
(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-m-
ethoxy-benzoic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-40% AcCN:H.sub.2O (with 0.1% TFA)] to
give a 29% yield of product as a white solid. ESI-MS m/z 363
(MH).sup.+.
Example 29:
3-[2-(4-Amino-3-aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-di-
hydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00085##
Step 1. Synthesis of
4-tert-Butoxycarbonylamino-3-methanesulfonyloxy-piperidine-1-carboxylic
acid benzyl ester
To a solution of
4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid
benzyl ester (prepared in Example 20, step 4, 1.02 g, 2.91 mmol) in
ethyl acetate (8.6 mL) and DCM (8.0 mL) was added triethylamine
(0.51 mL, 3.66 mmol) under argon. The reaction was cooled to
0.degree. C. and methanesulfonyl chloride (0.29 mL, 3.75 mmol) was
added dropwise. The reaction was stirred at 0.degree. C. for 50
minutes then warmed to room temperature for 3 h. The reaction was
filtered, washed with ethyl acetate, and concentrated to provide
crude product which was carried to the next step without
purification. ESI-MS m/z 429 (MH).sup.+.
Step 2. Synthesis of
4-tert-Butoxycarbonylamino-3-cyano-piperidine-1-carboxylic acid
benzyl ester
Tetrabutylammonium cyanide (1.57 g, 5.85 mmol) was added to a
solution of
4-tert-butoxycarbonylamino-3-methanesulfonyloxy-piperidine-1-carboxylic
acid benzyl ester (1.25 g, 2.91 mmol) in toluene (50 mL) under
argon and the reaction was heated at 80.degree. C. for 16.5 h. The
reaction was diluted with ethyl acetate and washed with brine
(2.times.). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to afford crude product which was
carried to the next step without purification. ESI-MS m/z 360
(MH).sup.+.
Step 3.
4-tert-Butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-pip-
eridine-1-carboxylic acid benzyl ester
A solution of
4-tert-Butoxycarbonylamino-3-cyano-piperidine-1-carboxylic acid
benzyl ester (1.05 g, 2.91 mmol) in (50 mL) under argon was cooled
to 0.degree. C. Nickel (II) chloride hexahydrate (0.312 g, 1.31
mmol) and di-tert-butyldicarbonate (1.09 g, 4.99 mmol) were added
followed by portionwise addition of sodium borohydride (0.739 g,
19.5 mmol) over 10 minutes. The reaction was stirred at 0.degree.
C. for 30 minutes then warmed to room temperature for 34 h.
Diethylenetriamine (0.5 mL) was added and the reaction was
concentrated to dryness. The residue was suspended in ethyl acetate
and washed with 0.25N HCl, saturated NaHCO.sub.3, and brine. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give 1.12 g of crude product which was carried to
the next step without purification. ESI-MS m/z 464 (MH).sup.+. Step
4. Synthesis of
[3-(tert-Butoxycarbonylamino-methyl)-piperidin-4-yl]-carbamic acid
tert-butyl ester.
A solution of
4-tert-Butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-piperidine-
-1-carboxylic acid benzyl ester (1.12 g, 2.42 mmol) in methanol (24
mL) was purged with argon for 5 minutes. Pd(OH).sub.2 (0.113 g, 20%
on carbon) was added, the flask evacuated, and the reaction placed
under a hydrogen atmosphere for 18 h. The reaction was filtered
through a Celite-plugged filter frit, washed with methanol and DCM,
and concentrated in vacuo to afford 0.810 g of crude product.
ESI-MS m/z 330 (MH).sup.+.
Step 5. Synthesis of
3-[2-{2-[4-tert-Butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-p-
iperidin-1-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6-
.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
[3-(tert-Butoxycarbonylamino-methyl)-piperidin-4-yl]-carbamic acid
tert-butyl ester following the procedure described in Step 2 of
Example 24. The crude product was purified by a reverse phase
preparative HPLC [Phenomenex Luna, 5 .mu.m, 30.times.75 mm, 5-100%
AcCN:H.sub.2O (with 0.1% TFA)] to give a 16% yield of product.
ESI-MS m/z 799 (MH).sup.+.
Step 6. Synthesis of
3-[2-(4-Amino-3-aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-di-
hydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-tert-Butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-p-
iperidin-1-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6-
.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
and BCl.sub.3 following the procedure described in Step 5 of
Example 1. The crude product was purified by reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-30% AcCN:H.sub.2O (with 0.1% TFA)] to give a 10% yield of product
as a white solid. ESI-MS m/z 377 (MH).sup.+.
Example 30:
3-{2-[4-(2-Amino-ethylamino)-piperidin-1-yl]-acetylamino}-2-hydroxy-3,4-d-
ihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00086##
Step 1. Synthesis of
4-(2-tert-Butoxycarbonylamino-ethylamino)-piperidine-1-carboxylic
acid benzyl ester
A mixture of 4-amino-1-N-Cbz-piperidine (0.683 g, 2.91 mmol) and
N-Boc-2-aminoacetaldehyde (0.463 g, 2.91 mmol) in methanol (12 mL)
was stirred under argon at room temperature for 17 h. Sodium
borohydride (0.220 g, 5.82 mmol) was added and the reaction stirred
for additional 7 h. The reaction was quenched with water and
extracted with DCM (2.times.). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Flash chromatography (0-100% EtOAc/hexane then 5-10%
CH.sub.3OH:DCM) provided 0.250 g (23%) of product. ESI-MS m/z 378
(MH).sup.+.
Step 2. Synthesis of
4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-piperidi-
ne-1-carboxylic acid benzyl ester
Triethylamine (0.16 mL, 1.15 mmol) and di-tert-butyldicarbonate
(0.178 g, 0.816 mmol) were added to a solution of
4-(2-tert-Butoxycarbonylamino-ethylamino)-piperidine-1-carboxylic
acid benzyl ester (0.250 g, 0.662 mmol) in DCM (7 mL) under argon.
The reaction was stirred at room temperature for 21.5 h. The
reaction was quenched with brine and extracted with DCM (2.times.).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered, and concentrated to afford crude product which was
carried to the next step without purification. ESI-MS m/z 478
(MH).sup.+.
Step 3. Synthesis of
(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl-carbamic acid
tert-butyl ester
A solution of
4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-piperidi-
ne-1-carboxylic acid benzyl ester (0.377 g, 0.789 mmol) in methanol
(8.0 mL) was purged with argon for 5 minutes. Pd(OH).sub.2 (0.062
g, 20% on carbon) was added, the flask evacuated, and the reaction
placed under a hydrogen atmosphere for 18 h. The reaction was
filtered through a Celite-plugged filter frit, washed with methanol
and DCM, and concentrated in vacuo to afford 0.267 g of crude
product. ESI-MS m/z 344 (MH).sup.+.
Step 4. Synthesis of
3-[2-(2-{4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-
-piperidin-1-yl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo-
[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl-carbamic acid
tert-butyl ester following the procedure described in Step 2 of
Example 24. The crude product was purified by a reverse phase
preparative HPLC [Phenomenex Luna, 5 .mu.m, 30.times.75 mm, 5-100%
AcCN:H.sub.2O (with 0.1% TFA)] to give a 21% yield of product.
ESI-MS m/z 813 (MH).sup.+.
Step 5. Synthesis of
3-{2-[4-(2-Amino-ethylamino)-piperidin-1-yl]-acetylamino}-2-hydroxy-3,4-d-
ihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-(2-{4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-
-piperidin-1-yl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo-
[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester and BCl.sub.3 following the procedure described in Step 5 of
Example 1. The crude product was purified by reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-30% AcCN:H.sub.2O (with 0.1% TFA)] to give a 16% yield of product
as a white solid. ESI-MS m/z 391 (MH).sup.+.
Example 31:
3-{3-[1-(2-Amino-ethyl)-piperidin-4-yl]-propionylamino}-2-hydroxy-3,4-dih-
ydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00087##
Step 1. Synthesis of
3-[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl]-propionic
acid
Palladium (0.130 g, 10% on carbon) was added to a mixture of
3-piperidin-4-yl-propionic acid (0.403 g, 2.56 mmol) and
(2-Oxo-ethyl)-carbamic acid tert-butyl ester (0.417 g, 2.62 mmol)
in methanol (5.0 mL) under argon. The flask was evacuated and the
reaction placed under a hydrogen atmosphere for 21 h. The reaction
was filtered through a Celite-plugged filter frit, washed with
methanol and DCM, and concentrated in vacuo to afford 0.775 g of
crude product. ESI-MS m/z 323 (M+Na).sup.+.
Step 2. Synthesis of
3-[2-{3-[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl]-propionylam-
ino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-eth-
yl]-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
3-[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl]-propionic
acid following the procedure described in Step 1 of Example 8. The
crude product was purified by a reverse phase column [Biotage Snap
C18 30 g, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give a 31% yield
of product. ESI-MS m/z 712 (MH).sup.+.
Step 3. Synthesis of
3-{3-[1-(2-Amino-ethyl)-piperidin-4-yl]-propionylamino}-2-hydroxy-3,4-dih-
ydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{3-[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl]-propionylam-
ino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-eth-
yl]-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-30% AcCN:H.sub.2O (with 0.1% TFA)]
to give a 5% yield of product as a white solid. ESI-MS m/z 390
(MH).sup.+.
Example 32:
2-Hydroxy-3-(2-piperidin-4-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]ox-
aborinine-8-carboxylic acid
##STR00088##
Step 1. Synthesis of tert-butyl
4-(2-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-
-3,5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2,6]dec-4-yl)ethylamino)-2-oxoethyl-
)piperidine-1-carboxylate
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid following the
procedure described in Step 1 of Example 8. The crude product was
purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1
to 1:2). ESI-MS m/z 655.1 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-(2-piperidin-4-yl-acetylamino)-3,4-dihydro-2H-benzo[e][1,2]ox-
aborinine-8-carboxylic acid
Prepared from tert-butyl
4-(2-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-
-3,5-dioxa-4-bora-tricyclo[6.1.1.0.sup.26]dec-4-yl)ethylamino)-2-oxoethyl)-
piperidine-1-carboxylate and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-30% AcCN:H.sub.2O (with 0.1% TFA)] to afford
product as a white solid. ESI-MS m/z 333 (MH).sup.+.
Example 33:
3-[2-(1-Carbamimidoyl-piperidin-4-yl)-acetylamino]-2-hydroxy-3,4-dihydro--
2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00089##
Step 1. Synthesis of
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-piperidine-
-1-carboxylic acid benzyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
2-(1-(benzyloxycarbonyl)piperidin-4-yl)acetic acid following the
procedure described in Step 1 of Example 8. The crude product was
purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1
to 1:2). ESI-MS m/z 689 (MH).sup.+.
Step 2. Synthesis of
2-Methoxy-3-[2-(2-piperidin-4-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid
tert-butyl ester
Palladium (0.039 g, 10% on carbon) was added to a solution of
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-piperidine-
-1-carboxylic acid benzyl ester (0.437 g, 0.635 mmol) in methanol
(6.7 mL) under argon. The flask was evacuated and the reaction
placed under a hydrogen atmosphere for 16 h. The reaction was
filtered through a Celite-plugged filter frit, washed with methanol
and DCM, and concentrated in vacuo to afford 0.361 g of crude
product. ESI-MS m/z 555 (MH).sup.+.
Step 3. Synthesis of
3-[2-{2-[1-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-pip-
eridin-4-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1-
.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester
Triethylamine (0.03 mL, 0.215 mmol) and
N,N'-di-Boc-1H-pyrazole-1-carboxamide (0.200 g, 0.644 mmol) were
added to a solution of
2-Methoxy-3-[2-(2-piperidin-4-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid
tert-butyl ester (0.120 g, 0.216 mmol) in methanol (4.2 mL) under
argon and stirred at room temperature for 17 h. The reaction was
concentrated to afford crude product which was carried to the next
step without purification. ESI-MS m/z 797 (MH).sup.+.
Step 4. Synthesis of
3-[2-(1-Carbamimidoyl-piperidin-4-yl)-acetylamino]-2-hydroxy-3,4-dihydro--
2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[1-(tert-Butoxycarbonylamino-tert-butoxycarbonylimino-methyl)-pip-
eridin-4-yl]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1-
.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester
and BCl.sub.3 following the procedure described in Step 5 of
Example 1. The crude product was purified by reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-50% AcCN:H.sub.2O (with 0.1% TFA)] to afford a 10% yield of
product as a white solid. ESI-MS m/z 375 (MH).sup.+.
Example 34:
3-{3-[1-(2-Guanidino-ethyl)-piperidin-4-yl]-propionylamino}-2-hydroxy-3,4-
-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00090##
Step 1. Synthesis of
3-{3-[1-(2-Di-tert-butoxycarbonyl-guanidino-ethyl)-piperidin-4-yl]-propio-
nylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic
acid
Prepared from
3-{3-[1-(2-Amino-ethyl)-piperidin-4-yl]-propionylamino}-2-hydroxy-3,4-dih-
ydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid following the
procedure described in Step 3 of Example 33. The crude product was
carried to the next step without purification. ESI-MS m/z 632
(MH).sup.+.
Step 2. Synthesis of
3-{3-[1-(2-Guanidino-ethyl)-piperidin-4-yl]-propionylamino}-2-hydroxy-3,4-
-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
A solution of
3-{3-[1-(2-Di-tert-butoxycarbonyl-guanidino-ethyl)-piperidin-4-yl]-propio-
nylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic
acid (0.013 g, 0.020 mmol) in hydrochloric acid (4.0N in
1,4-dioxane, 1.9 mL, 7.60 mmol) was stirred at room temperature for
26 h. The reaction was concentrated and the crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
afford a 32% yield of product as a white solid. ESI-MS m/z 432
(MH).sup.+.
Example 35:
3-[2-(1-Cyanomethyl-piperidin-4-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00091##
Step 1. Synthesis of
3-[2-[2-(1-Cyanomethyl-piperidin-4-yl)-acetylamino]-2-(2,9,9-trimethyl-3,-
5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic
acid tert butyl ester
To a solution of
2-Methoxy-3-[2-(2-piperidin-4-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid
tert-butyl ester (Step 2, Example 33, 0.250 g, 0.451 mmol) in
acetonitrile (5.0 mL) was added potassium carbonate (0.132 g, 0.955
mmol) and bromoacetonitrile (0.08 mL, 1.15 mmol) under argon. The
reaction was stirred at room temperature for 42 h. The reaction was
quenched with water and extracted with diethyl ether (3.times.).
The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude product was carried to the
next step without purification. ESI-MS m/z 594 (MH).sup.+.
Step 2. Synthesis of
3-[2-(1-Cyanomethyl-piperidin-4-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-[2-(1-Cyanomethyl-piperidin-4-yl)-acetylamino]-2-(2,9,9-trimethyl-3,-
5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic
acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to provide a
44% yield of product as a white solid. ESI-MS m/z 372 (MH).
Example 36:
3-{2-[4-(2-Amino-ethyl)-2-oxo-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00092##
Step 1. Synthesis of
[4-(2-tert-Butoxycarbonylamino-ethyl)-2-oxo-piperazin-1-yl]-acetic
acid
Palladium (0.161 g, 10% on carbon) was added to a mixture of
2-Oxo-1-piperazineacetic acid (0.497 g, 3.14 mmol) and
(2-Oxo-ethyl)-carbamic acid tert-butyl ester (0.503 g, 3.16 mmol)
in methanol (6.2 mL) under argon. The flask was evacuated and the
reaction placed under a hydrogen atmosphere for 22 h. The reaction
was filtered through a Celite-plugged filter frit, washed with
methanol and DCM, and concentrated in vacuo to afford crude product
which was carried to the next step without purification. ESI-MS m/z
324 (M+Na).sup.+.
Step 2. Synthesis of
3-[2-{2-[4-(2-tert-Butoxycarbonylamino-ethyl)-2-oxo-piperazin-1-yl]-acety-
lamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)--
ethyl]-2-methoxy-benzoic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
[4-(2-tert-Butoxycarbonylamino-ethyl)-2-oxo-piperazin-1-yl]-acetic
acid following the procedure described in Step 1 of Example 8. The
crude product was purified by reverse phase column [C18, 30 g,
5-100% AcCN:H.sub.2O (with 0.1% TFA)] to afford a 28% yield of
product as a white solid. ESI-MS m/z 713 (MH).sup.+.
Step 3. Synthesis of
3-{2-[4-(2-Amino-ethyl)-2-oxo-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[4-(2-tert-Butoxycarbonylamino-ethyl)-2-oxo-piperazin-1-yl]-acety-
lamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)--
ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3
following the procedure described in Step 5 of Example 1. The crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O
(with 0.1% TFA)] to afford product as a white solid. ESI-MS m/z 391
(MH).sup.+.
Example 37:
3-[2-(3-Guanidinomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00093##
Step 1. Synthesis of
3-{3-[1-(2-Di-tert-butoxycarbonyl-guanidino-ethyl)-piperidin-4-yl]-propio-
nylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic
acid
Prepared from
3-[2-(3-Aminomethyl-piperidin-1-yl)-acetylamino]-2-hydroxy-3,4-dihydro-2H-
-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 19) following
the procedure described in Step 3 of Example 33. The crude product
was carried to the next step without purification. ESI-MS m/z 604
(MH).sup.+.
Step 2. Synthesis of
3-{3-[1-(2-Guanidino-ethyl)-piperidin-4-yl]-propionylamino}-2-hydroxy-3,4-
-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-{3-[1-(2-Di-tert-butoxycarbonyl-guanidino-ethyl)-piperidin-4-yl]-propio-
nylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic
acid and hydrochloric acid following the procedure described in
Step 2 of Example 34. The reaction was concentrated and the crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with
0.1% TFA)] to afford a 28% yield of product as a white solid.
ESI-MS m/z 404 (MH).sup.+.
Example 38:
3-{2-[4-(2-Guanidino-ethyl)-2-oxo-piperazin-1-yl]-acetylamino}-2-hydroxy--
3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00094##
Step 1. Synthesis of
3-{2-[4-(2-Di-tert-butoxycarbonyl-guanidino-ethyl)-2-oxo-piperazin-1-yl]--
acetylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxyli-
c acid
Prepared from
3-{2-[4-(2-Amino-ethyl)-2-oxo-piperazin-1-yl]-acetylamino}-2-hydroxy-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 36)
following the procedure described in Step 3 of Example 33. The
crude product was carried to the next step without purification.
ESI-MS m/z 633 (MH).sup.+.
Step 2.
3-{2-[4-(2-Guanidino-ethyl)-2-oxo-piperazin-1-yl]-acetylamino}-2-h-
ydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic
acid
Prepared from
3-{2-[4-(2-Di-tert-butoxycarbonyl-guanidino-ethyl)-2-oxo-piperazin-1-yl]--
acetylamino}-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxyli-
c acid and hydrochloric acid following the procedure described in
Step 2 of Example 34. The reaction was concentrated and the crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with
0.1% TFA)] to afford a 63% yield of product as a white solid.
ESI-MS m/z 433 (MH).sup.+.
Example 39:
2-Hydroxy-3-[2-(piperidin-4-yloxy)-acetylamino]-3,4-dihydro-2H-benzo[e][1-
,2]oxaborinine-8-carboxylic acid
##STR00095##
Step 1. Synthesis of
4-Ethoxycarbonylmethoxy-piperidine-1-carboxylic acid tert-butyl
ester
Sodium hydride (60%, 0.480 g, 12.0 mmol) was added to a solution of
1-Boc-4-hydroxypiperidine (1.61 g, 8.00 mmol) in THF (70 mL) under
argon and the reaction mixture was stirred at room temperature for
25 minutes. Ethyl bromoacetate (2.0 mL, 18.0 mmol) was added and
the reaction stirred for 17 h. The reaction was quenched with
saturated NaHCO.sub.3 and extracted with ethyl acetate (2.times.).
The combined organic layers were washed with H.sub.2O and brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford
crude product which was carried to the next step without
purification. ESI-MS m/z 310 (M+Na).sup.+.
Step 2. Synthesis of 4-Carboxymethoxy-piperidine-1-carboxylic acid
tert-butyl ester
Sodium hydroxide (1M, 31 mL, 31.0 mmol) was added to a solution of
4-Ethoxycarbonylmethoxy-piperidine-1-carboxylic acid tert-butyl
ester (2.30 g, 8.00 mmol) in methanol (65 mL) and THF (15 mL). The
reaction was stirred at room temperature for 18 h. The reaction was
concentrated to remove methanol and THF and the remaining aqueous
layer was extracted with diethyl ether (2.times.). The aqueous
layer was acidified to pH.about.1 with 3N HCl (.about.10.5 mL).
Brine was added and extracted with ethyl acetate (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated to afford 0.610 g of product for a 29% yield over
two steps. ESI-MS m/z 282 (M+Na).sup.+.
Step 3. Synthesis of
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methoxy}-piperidin-
e-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
4-Carboxymethoxy-piperidine-1-carboxylic acid tert-butyl ester
following the procedure described in Step 1 of Example 8. Flash
chromatography (0-100% EtOAc/hexane) provided 0.378 g (31%) of
product as an off white solid. ESI-MS m/z 671 (MH).sup.+.
Step 4. Synthesis of
2-Hydroxy-3-[2-(piperidin-4-yloxy)-acetylamino]-3,4-dihydro-2H-benzo[e][1-
,2]oxaborinine-8-carboxylic acid
Prepared from
4-{[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-dio-
xa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methoxy}-piperidin-
e-1-carboxylic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-60% AcCN:H.sub.2O (with 0.1% TFA)] to
afford product as a white solid. ESI-MS m/z 349 (MH).sup.+.
Example 40:
2-Hydroxy-3-[2-(piperidin-4-ylamino)-acetylamino]-3,4-dihydro-2H-benzo[e]-
[1,2]oxaborinine-8-carboxylic acid
##STR00096##
Step 1. Synthesis of
4-(Ethoxycarbonylmethyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester
To a solution of 4-amino-1-Boc-piperidine (0.817 g, 4.08 mmol) in
acetonitrile (5.0 mL) were added diisopropylethylamine (1.4 mL,
8.04 mmol) and ethyl bromoacetate (0.45 mL, 4.06 mmol). The
resulting suspension was stirred under argon at room temperature
for 17 h. The reaction was concentrated in vacuo. The residue was
diluted with H.sub.2O and extracted with DCM (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated to provide crude product which was carried forward
without purification. ESI-MS m/z 287 (MH).
Step 2. Synthesis of
4-(Benzyloxycarbonyl-ethoxycarbonylmethyl-amino)-piperidine-1-carboxylic
acid tert-butyl ester
A solution of
4-(Ethoxycarbonylmethyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester (1.09 g, 3.81 mmol) in DCM (15 mL) under argon was
cooled to -10.degree. C. Triethylamine (2.8 mL, 20.1 mmol) and
benzyl chloroformate (1.4 mL, 9.67 mmol) were added slowly and the
reaction was allowed to warm to room temperature and stir for 71 h.
The reaction was diluted with DCM and washed successively with
H.sub.2O, saturated NaHCO.sub.3, and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford
crude product which was carried forward without purification.
ESI-MS m/z 421 (MH).
Step 3. Synthesis of
4-(Benzyloxycarbonyl-carboxymethyl-amino)-piperidine-1-carboxylic
acid tert-butyl ester
Prepared from
4-(Benzyloxycarbonyl-ethoxycarbonylmethyl-amino)-piperidine-1-carboxylic
acid tert-butyl ester following the procedure described in Step 2
of Example 39. The crude product was carried forward without
purification. ESI-MS m/z 415 (M+Na).
Step 4. Synthesis of
4-(Benzyloxycarbonyl-{[2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-
-methyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
4-(Benzyloxycarbonyl-carboxymethyl-amino)-piperidine-1-carboxylic
acid tert-butyl ester following the procedure described in Step 1
of Example 8. Flash chromatography (0-80% EtOAc/hexane) provided
0.202 g (14%) of product as a white solid. ESI-MS m/z 804
(MH).sup.+.
Step 5. Synthesis of
4-({[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-amino)-pi-
peridine-1-carboxylic acid tert-butyl ester
A solution of
4-(Benzyloxycarbonyl-{[2-(3-tert-butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-
-methyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester
(0.202 g, 0.251 mmol) in methanol (4.0 mL) was purged with argon
for -5 minutes. Palladium on carbon (10%, 0.020 g) was added, flask
evacuated, and the reaction stirred under H.sub.2 atmosphere for 16
h. The reaction was filtered through a Celite-plugged filter frit,
washed with methanol and DCM, and concentrated to give the crude
product which was carried forward without purification. ESI-MS m/z
670 (MH).sup.+.
Step 6. Synthesis of
2-Hydroxy-3-[2-(piperidin-4-ylamino)-acetylamino]-3,4-dihydro-2H-benzo[e]-
[1,2]oxaborinine-8-carboxylic acid
Prepared from
4-({[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-amino)-pi-
peridine-1-carboxylic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-30% AcCN:H.sub.2O (with 0.1% TFA)]
to afford product as a white solid.
ESI-MS m/z 348 (MH).sup.+.
Example 41:
3-{2-[1-(2-Amino-ethyl)-piperidin-4-yl]-acetylamino}-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00097##
Step 1. Synthesis of
3-[2-{2-[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl]-acetylamino-
}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester
To a solution of
2-Methoxy-3-[2-(2-piperidin-4-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid
tert-butyl ester (Step 2, Example 33, 0.102 g, 0.184 mmol) in
methanol (2.5 mL) was added (2-Oxo-ethyl)-carbamic acid tert-butyl
ester (0.060 g, 0.377 mmol) followed by palladium on carbon (10%,
0.017 g). The flask was evacuated and the reaction placed under
H.sub.2 for 18 h. The reaction was filtered through a
Celite-plugged filter frit, washed with methanol and DCM, and
concentrated. The crude product was carried forward without
purification. ESI-MS m/z 698 (MH).sup.+.
Step 2. Synthesis of
3-{2-[1-(2-Amino-ethyl)-piperidin-4-yl]-acetylamino}-2-hydroxy-3,4-dihydr-
o-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-yl]-acetylamino-
}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-
-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-40% AcCN:H.sub.2O (with 0.1% TFA)]
to afford a 38% yield of product as a white solid. ESI-MS m/z 376
(MH).sup.+.
Example 42:
3-{2-[1-(3-Amino-propyl)-piperidin-4-yl]-acetylamino}-2-hydroxy-3,4-dihyd-
ro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00098##
Step 1. Synthesis of
3-[2-{2-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-acetylamin-
o}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl-
]-2-methoxy-benzoic acid tert-butyl ester
Potassium carbonate (0.030 g, 0.217 mmol) was added to a solution
of
2-Methoxy-3-[2-(2-piperidin-4-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid
tert-butyl ester (Step 2, Example 33, 0.078 g, 0.141 mmol) and
3-(Boc-amino)propyl bromide (0.065 g, 0.273 mmol) in DMF (2.5 mL).
The reaction was sealed and heated at 60.degree. C. for 16 h. The
reaction was cooled to room temperature, quenched with H.sub.2O,
and extracted with ethyl acetate (2.times.). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to provide crude product which was
carried forward without purification. ESI-MS m/z 712
(MH).sup.+.
Step 2. Synthesis of
3-{2-[1-(3-Amino-propyl)-piperidin-4-yl]-acetylamino}-2-hydroxy-3,4-dihyd-
ro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-{2-[1-(3-tert-Butoxycarbonylamino-propyl)-piperidin-4-yl]-acetylamin-
o}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl-
]-2-methoxy-benzoic acid tert-butyl ester and BCl.sub.3 following
the procedure described in Step 5 of Example 1. The crude product
was purified by reverse phase preparative HPLC [Waters Sunfire C18
OBD, 5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)]
to afford a 15% yield of product as a white solid. ESI-MS m/z 390
(MH).sup.+.
Example 43:
2-Hydroxy-3-[2-(methyl-piperidin-4-yl-amino)-acetylamino]-3,4-dihydro-2H--
benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00099##
Step 1. Synthesis of
4-(Ethoxycarbonylmethyl-methyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester
To a solution of
4-(Ethoxycarbonylmethyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester (Step 2, Example 40, 1.09 g, 3.81 mmol) in DCM (95
mL) under argon was added formaldehyde (37% in H.sub.2O, 3.2 mL,
39.4 mmol), acetic acid (0.44 mL, 7.69 mmol), and sodium
triacetoxyborohydride (1.61 g, 7.60 mmol). The reaction was stirred
at room temperature for 20 h. The reaction was quenched with ice
cold H.sub.2O and extracted with DCM (2.times.). The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated to provide crude product which was
carried forward without purification. ESI-MS m/z 323 (M+Na)+.
Step 2. Synthesis of
4-(Carboxymethyl-methyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester
Prepared from
4-(Ethoxycarbonylmethyl-methyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester following the procedure described in Step 2 of
Example 39. The crude product was carried forward without
purification. ESI-MS m/z 295 (M+Na).sup.+.
Step 3. Synthesis of
4-({[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-methyl-am-
ino)-piperidine-1-carboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
4-(Carboxymethyl-methyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester following the procedure described in Step 1 of
Example 8. The crude product was purified by reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm,
5-100% AcCN:H.sub.2O (with 0.1% TFA)] to give an 8% yield of
product as a white solid. ESI-MS m/z 684 (MH).sup.+.
Step 4. Synthesis of
2-Hydroxy-3-[2-(methyl-piperidin-4-yl-amino)-acetylamino]-3,4-dihydro-2H--
benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
4-({[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-di-
oxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-methyl}-methyl-am-
ino)-piperidine-1-carboxylic acid tert-butyl ester and BCl.sub.3
following the procedure described in Step 5 of Example 1. The crude
product was purified by reverse phase preparative HPLC [Waters
Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-40% AcCN:H.sub.2O (with
0.1% TFA)] to afford a 27% yield of product as a white solid.
ESI-MS m/z 362 (MH).sup.+.
Example 44:
2-Hydroxy-3-[(piperidine-4-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]o-
xaborinine-8-carboxylic acid
##STR00100##
Step 1. Synthesis of
4-[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-piperidine-1-carbox-
ylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid following the
procedure described in Step 1 of Example 8. The crude product was
purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1
to 1:2). ESI-MS m/z 641 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[(piperidine-4-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]o-
xaborinine-8-carboxylic acid
Prepared
4-[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-
-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylcarbamoyl]-piperidine-
-1-carboxylic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to
afford product as a white solid. ESI-MS m/z 319 (MH).sup.+.
Example 45:
2-Hydroxy-3-[2-(1-methyl-piperidin-4-yl)-acetylamino]-3,4-dihydro-2H-benz-
o[e][1,2]oxaborinine-8-carboxylic acid
##STR00101##
Step 1. Synthesis of
2-Methoxy-3-[2-[2-(1-methyl-piperidin-4-yl)-acetylamino]-2-(2,9,9-trimeth-
yl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic
acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
(1-Methyl-piperidin-4-yl)-acetic acid following the procedure
described in Step 1 of Example 8. The crude product was purified by
flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2).
ESI-MS m/z 569 (MH).sup.+.
Step 2. Synthesis of
2-Hydroxy-3-[2-(1-methyl-piperidin-4-yl)-acetylamino]-3,4-dihydro-2H-benz-
o[e][1,2]oxaborinine-8-carboxylic acid
Prepared
2-Methoxy-3-[2-[2-(1-methyl-piperidin-4-yl)-acetylamino]-2-(2,9,-
9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic
acid tert-butyl ester and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to afford
product as a white solid. ESI-MS m/z 347 (MH).sup.+.
Example 46:
(R)-3-(azetidine-3-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxa-
borinine-8-carboxylic acid
##STR00102##
Step 1. Synthesis of
3-[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.0.sup.2,6]dec-4-yl)-ethylcarbamoyl]-azetidine-1-ca-
rboxylic acid tert-butyl ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid and
1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid following the
procedure described in Step 1 of Example 8. The crude product was
purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1
to 1:2). ESI-MS m/z 655 (MH).sup.+.
Step 2. Synthesis of
(R)-3-(azetidine-3-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxa-
borinine-8-carboxylic acid
Prepared from
3-[2-(3-tert-Butoxycarbonyl-2-methoxy-phenyl)-1-(2,9,9-trimethyl-3,5-diox-
a-4-bora-tricyclo[6.1.1.0.sup.2'6]dec-4-yl)-ethylcarbamoyl]-azetidine-1-ca-
rboxylic acid tert-butyl ester and BCl.sub.3 following the
procedure described in Step 5 of Example 1. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 m, 19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to afford
product as a white solid. ESI-MS m/z 333 (MH).sup.+.
Example 47:
(R)-3-(1-(4-(dimethylamino)phenylcarbamoyl)azetidine-3-carboxamido)-2-hyd-
roxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00103##
Step 1. Synthesis of
(R)-3-(1-(4-(dimethylamino)phenylcarbamoyl)azetidine-3-carboxamido)-2-hyd-
roxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
To 10 mg of
(R)-3-(azetidine-3-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxa-
borinine-8-carboxylic acid (Step 2, Example 46) in 1 mL of DMF was
added 10 mg of 4-isocyanato-N,N-dimethylaniline. The resulting
reaction mixture was stirred at room temperature overnight. The
crude product was purified by reverse phase preparative HPLC
[Waters Sunfire C18 OBD, 5 .mu.m, 19.times.50 mm, 5-100%
AcCN:H.sub.2O (with 0.1% TFA)] to afford product as a white solid.
ESI-MS m/z 453 (MH).sup.+.
Example 48:
(R)-2-hydroxy-3-(1-(pyrimidin-2-yl)azetidine-3-carboxamido)-3,4-dihydro-2-
H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00104##
Step 1. Synthesis of
(R)-2-hydroxy-3-(1-(pyrimidin-2-yl)azetidine-3-carboxamido)-3,4-dihydro-2-
H-benzo[e][1,2]oxaborinine-8-carboxylic acid
To 10 mg of
(R)-3-(azetidine-3-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxa-
borinine-8-carboxylic acid (Step 2, Example 46) in 1 mL of DMF was
added 20 mg of 2-chloropyrimidine. The resulting reaction mixture
was stirred at 100.degree. C. for 5 h. The crude product was
purified by reverse phase preparative HPLC [Waters Sunfire C18 OBD,
5 .mu.m, 19.times.50 mm, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to
afford product as a white solid. ESI-MS m/z 369 (MH).
Example 49:
3-[(4-Amino-piperidine-4-carbonyl)-amino]-2-hydroxy-3,4-dihydro-2H-benzo[-
e][1,2]oxaborinine-8-carboxylic acid
##STR00105##
Step 1. Synthesis of tert-butyl
4-(benzyloxycarbonylamino)-4-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyph-
enyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2,6]dec-4-y-
l)ethylcarbamoyl)piperidine-1-carboxylate
Prepared from 4-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl)
piperidine-4-carboxylic acid and
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester following the procedure
described in Step 1 of Example 8. The crude product was purified by
flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2).
ESI-MS m/z 790 (MH).
Step 2. Synthesis of tert-butyl
4-amino-4-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trim-
ethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2'6]dec-4-yl)ethylcarbamoyl)pi-
peridine-1-carboxylate
Prepared from tert-butyl
4-(benzyloxycarbonylamino)-4-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyph-
enyl)-1-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2'6]dec-4-y-
l)ethylcarbamoyl)piperidine-1-carboxylate following procedure
described in Step 2 of Example 33. ESI-MS m/z 656 (MH).sup.+.
Step 3. Synthesis of
3-[(4-Amino-piperidine-4-carbonyl)-amino]-2-hydroxy-3,4-dihydro-2H-benzo[-
e][1,2]oxaborinine-8-carboxylic acid
Prepared from tert-butyl
4-amino-4-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trim-
ethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2,6]dec-4-yl)ethylcarbamoyl)pi-
peridine-1-carboxylate and BCl.sub.3 following the procedure
described in Step 5 of Example 1. The crude product was purified by
reverse phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to afford
product as a white solid. ESI-MS m/z 334 (MH).sup.+.
Example 50:
2-Hydroxy-3-[(piperazine-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]o-
xaborinine-8-carboxylic acid
##STR00106##
Step 1. Synthesis of 1-benzyl 4-tert-butyl
2-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,-
5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2'6]dec-4-yl)ethylcarbamoyl)piperazine-
-1,4-dicarboxylate
Prepared from
1-(benzyloxycarbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic
acid and
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-
-4-ylmethyl)-benzoic acid tert-butyl ester following the procedure
described in Step 1 of Example 8. The crude product was purified by
flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2).
ESI-MS m/z 776 (MH).sup.+.
Step 2. Synthesis of tert-butyl
3-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,-
5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2,6]dec-4-yl)ethylcarbamoyl)piperazine-
-1-carboxylate
Prepared from 1-benzyl 4-tert-butyl
2-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,-
5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2,6]dec-4-yl)ethylcarbamoyl)piperazine-
-1,4-dicarboxylate following procedure described in Step 2 of
Example 33. ESI-MS m/z 642 (MH).sup.+.
Step 3. Synthesis of
2-Hydroxy-3-[(piperazine-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[e][1,2]o-
xaborinine-8-carboxylic acid
Prepared from tert-butyl
3-((1R)-2-(3-(tert-butoxycarbonyl)-2-methoxyphenyl)-1-(2,9,9-trimethyl-3,-
5-dioxa-4-bora-tricyclo[6.1.1.0.sup.2'6]dec-4-yl)ethylcarbamoyl)piperazine-
-1-carboxylate and BCl.sub.3 following the procedure described in
Step 5 of Example 1. The crude product was purified by reverse
phase preparative HPLC [Waters Sunfire C18 OBD, 5 .mu.m,
19.times.50 mm, 5-50% AcCN:H.sub.2O (with 0.1% TFA)] to afford
product as a white solid. ESI-MS m/z 320 (MH).sup.+.
Example 51:
3-[(4-Dimethylamino-1-methyl-piperidine-4-carbonyl)-amino]-2-hydroxy-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00107##
Step 1. Synthesis of
3-[(4-Dimethylamino-1-methyl-piperidine-4-carbonyl)-amino]-2-hydroxy-3,4--
dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
To
3-[(4-Amino-piperidine-4-carbonyl)-amino]-2-hydroxy-3,4-dihydro-2H-ben-
zo[e][1,2]oxaborinine-8-carboxylic acid (Step 3, Example 49, 10.0
mg) in methanol (5 mL) was added formaldehyde (1.0 mL, 37%
solution), followed by 10% palladium on carbon (20 mg). The
reaction mixture was hydrogenated under H.sub.2 balloon for 3 h.
The reaction mixture was filtrated and the solvent was removed
under vacuum. The crude product was purified by reverse phase
preparative HPLC [Waters Sunfire C18 OBD, 5 m, 19.times.50 mm,
5-100% AcCN:H.sub.2O (with 0.1% TFA)] to afford product as a white
solid. ESI-MS m/z 376 (MH).sup.+.
Example 52:
3-{2-[1-(2-Amino-ethyl)-piperidin-4-ylamino]-acetylamino}-2-hydroxy-3,4-d-
ihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
##STR00108##
Step 1. Synthesis of
4-(Benzyloxycarbonylmethyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester
Potassium carbonate (2.35 g, 17.0 mmol) and benzyl bromoacetate
(0.74 mL, 4.67 mmol) were added to a solution of
4-amino-1-Boc-piperidine (0.850 g, 4.24 mmol) in acetonitrile (55
mL) under argon and stirred at room temperature for 20 h. The
reaction was diluted with ethyl acetate and washed with sat.
NaHCO.sub.3 and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
carried forward without purification. ESI-MS m/z 349
(MH).sup.+.
Step 2. Synthesis of
4-(Benzyloxycarbonyl-benzyloxycarbonylmethyl-amino)-piperidine-1-carboxyl-
ic acid tert-butyl ester
Triethylamine (2.1 mL, 15.1 mmol) and 4-(dimethylamino)pyridine
(0.262 g, 2.14 mmol) were added to a solution of
4-(Benzyloxycarbonylmethyl-amino)-piperidine-1-carboxylic acid
tert-butyl ester (1.48 g, 4.25 mmol) in DCM (42 mL) under argon.
The reaction mixture was cooled to 5.degree. C. for 20 min. Benzyl
chloroformate (1.3 mL, 8.90 mmol) was added slowly and the reaction
allowed to warm to room temperature and stir for 18 h. The reaction
was quenched with brine and extracted with DCM (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The crude product was purified by flash
chromatography on silica gel (0-40% EtOAc:Hexane). ESI-MS m/z 483
(MH).sup.+.
Step 3. Synthesis of
(Benzyloxycarbonyl-piperidin-4-yl-amino)-acetic acid benzyl
ester
To a solution of
4-(Benzyloxycarbonyl-benzyloxycarbonylmethyl-amino)-piperidine-1-carboxyl-
ic acid tert-butyl ester (0.860 g, 1.78 mmol) in DCM (15 mL) was
added hydrochloric acid (4.0N in 1,4-dioxane, 2.2 mL, 8.80 mmol)
and the reaction was stirred at room temperature for 17 h. The
reaction was concentrated in vacuo and carried forward without
purification. ESI-MS m/z 383 (MH).sup.+.
Step 4. Synthesis of
{Benzyloxycarbonyl-[1-(2-tert-butoxycarbonylamino-ethyl)-piperidin-4-yl]--
amino}-acetic acid benzyl ester
A solution of (Benzyloxycarbonyl-piperidin-4-yl-amino)-acetic acid
benzyl ester (0.681 g, 1.78 mmol) and (2-oxo-ethyl)-carbamic acid
tert-butyl ester (0.325 g, 2.04 mmol) in methanol (12 mL) was
stirred under argon for 7 h. Sodium triacetoxyborohydride (0.554 g,
2.61 mmol) was added and the reaction stirred overnight. The
reaction was quenched with sat. NaHCO.sub.3 and extracted with
ethyl acetate (3.times.). The combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude product was purified by flash
chromatography on silica gel (0-100% EtOAc:Hexane). ESI-MS m/z 526
(MH).
Step 5. Synthesis of
[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-ylamino]-acetic
acid
A solution of
{Benzyloxycarbonyl-[1-(2-tert-butoxycarbonylamino-ethyl)-piperidin-4-yl]--
amino}-acetic acid benzyl ester (0.273 g, 0.519 mmol) in methanol
(5.5 mL) was purged with argon for 5 min. Palladium on carbon (10%,
0.052 g) was added, flask evacuated, and the reaction stirred under
a H.sub.2 atmosphere at room temperature for 18 h. The reaction was
filtered through a Celite-plugged filter frit, washed with methanol
and DCM, and concentrated. The crude product was carried forward
without purification. ESI-MS m/z 302 (MH).sup.+.
Step 6. Synthesis of
{tert-Butoxycarbonyl-[1-(2-tert-butoxycarbonylamino-ethyl)-piperidin-4-yl-
]-amino}-acetic acid
To a solution of
[1-(2-tert-Butoxycarbonylamino-ethyl)-piperidin-4-ylamino]-acetic
acid (0.156 g, 0.518 mmol) in THF (2.0 mL) and H.sub.2O (2.0 mL)
was added di-tert-butyl dicarbonate (0.126 g, 0.577 mmol) and
sodium bicarbonate (0.058 g, 0.690 mmol). The reaction was stirred
at room temperature for 17 h. The reaction was quenched with 3N
HCl, diluted with brine, and extracted with ethyl acetate
(3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was
carried forward without purification. ESI-MS m/z 424
(M+Na).sup.+.
Step 7. Synthesis of
3-[2-(2-{tert-Butoxycarbonyl-[1-(2-tert-butoxycarbonylamino-ethyl)-piperi-
din-4-yl]-amino}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo-
[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester
Prepared from
2-Methoxy-3-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-y-
lmethyl)-benzoic acid tert-butyl ester and
{tert-Butoxycarbonyl-[1-(2-tert-butoxycarbonylamino-ethyl)-piperidin-4-yl-
]-amino}-acetic acid following the procedure described in Step 1 of
Example 8. The crude product was purified by reverse phase column
[C18, 30 g, 5-100% AcCN:H.sub.2O (with 0.1% TFA)] to afford product
as a white solid. ESI-MS m/z 813 (MH).sup.+.
Step 8. Synthesis of
3-{2-[1-(2-Amino-ethyl)-piperidin-4-ylamino]-acetylamino}-2-hydroxy-3,4-d-
ihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid
Prepared from
3-[2-(2-{tert-Butoxycarbonyl-[1-(2-tert-butoxycarbonylamino-ethyl)-piperi-
din-4-yl]-amino}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo-
[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl
ester and BCl.sub.3 following the procedure described in Step 5 of
Example 1. The crude product was purified by reverse phase
preparative HPLC [Phenomenex Luna C18, 5 .mu.m, 19.times.50 mm,
5-40% AcCN:H.sub.2O (with 0.1% TFA)] to afford product as a white
solid. ESI-MS m/z 391 (MH).sup.+.
TABLE-US-00001 TABLE 1 Examples of Compounds ESI-MS (m/z) Example
Structure MW for [MH]+ 1 ##STR00109## 347 348 2 ##STR00110## 410
411 3 ##STR00111## 404 405 4 ##STR00112## 333 334 5 ##STR00113##
361 362 6 ##STR00114## 333 334 7 ##STR00115## 333 334 8
##STR00116## 347 348 9 ##STR00117## 333 334 10 ##STR00118## 347 348
11 ##STR00119## 347 348 12 ##STR00120## 348 349 13 ##STR00121## 347
348 14 ##STR00122## 361 362 15 ##STR00123## 416 417 16 ##STR00124##
376 377 17 ##STR00125## 390 391 18 ##STR00126## 377 378 19
##STR00127## 361 362 20 ##STR00128## 377 378 21 ##STR00129## 377
378 22 ##STR00130## 361 362 23 ##STR00131## 347 348 24 ##STR00132##
363 364 25 ##STR00133## 391 392 26 ##STR00134## 363 364 27
##STR00135## 418 419 28 ##STR00136## 362 363 29 ##STR00137## 376
377 30 ##STR00138## 390 391 31 ##STR00139## 389 390 32 ##STR00140##
332 333 33 ##STR00141## 374 375 34 ##STR00142## 431 432 35
##STR00143## 371 372 36 ##STR00144## 390 391 37 ##STR00145## 403
404 38 ##STR00146## 432 433 39 ##STR00147## 348 349 40 ##STR00148##
347 348 41 ##STR00149## 375 376 42 ##STR00150## 389 390 43
##STR00151## 361 362 44 ##STR00152## 318 319 45 ##STR00153## 346
347 46 ##STR00154## 332 333 47 ##STR00155## 452 453 48 ##STR00156##
368 369 49 ##STR00157## 333 334 50 ##STR00158## 319 320 51
##STR00159## 375 376 52 ##STR00160## 390 391 53 ##STR00161## 54
##STR00162## 55 ##STR00163## 56 ##STR00164## 57 ##STR00165## 58
##STR00166## 59 ##STR00167## 60 ##STR00168## 61 ##STR00169## 62
##STR00170## 63 ##STR00171## 64 ##STR00172## 65 ##STR00173## 66
##STR00174## 67 ##STR00175## 68 ##STR00176## 69 ##STR00177## 70
##STR00178## 71 ##STR00179## 72 ##STR00180## 73 ##STR00181## 74
##STR00182## 75 ##STR00183## 76 ##STR00184## 77 ##STR00185## 78
##STR00186## 79 ##STR00187## 80 ##STR00188## 81 ##STR00189## 82
##STR00190## 83 ##STR00191## 84 ##STR00192## 85 ##STR00193##
Example 53: Parenteral Composition of a Compound of Formula I or
Formula Ia
To prepare a parenteral pharmaceutical composition suitable for
administration by injection, 100 mg of a compound of Formula I or
Formula Ia, or a water soluble pharmaceutically acceptable salt
thereof, is dissolved in DMSO and then mixed with 10 ml of 0.9%
sterile saline solution. The mixture is incorporated into a dosage
unit suitable for administration by injection.
Example 54: Oral Composition of a Compound of Formula I or Formula
Ia
To prepare a pharmaceutical composition for oral delivery, 400 mg
of a compound of Formula I or Formula Ia and the following
ingredients are mixed intimately and pressed into single scored
tablets.
TABLE-US-00002 Tablet Formulation Quantity per Ingredient tablet mg
compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120
magnesium stearate 5
The following ingredients are mixed intimately and loaded into a
hard-shell gelatin capsule.
TABLE-US-00003 Capsule Formulation Quantity per Ingredient capsule
mg compound 200 lactose spray dried 148 magnesium stearate 2
Biological Examples
Example I: Experimental Method for .beta.-Lactamase Enzyme
Assays
Isolation of .beta.-Lactamases
For SHV-5, Kpc-2, p99AmpC and OXA-1 .beta.-lactamases, E. coli
BL21(DE3) bacterial cells carrying expression plasmids (expressed
as native untagged proteins) for the individual .beta.-lactamases
were grown in 1 L of Superbroth (Teknova Inc. Hollister, Calif.)
supplemented with 100 .mu.g/ml kanamycin selection and 1.times.5052
(0.5% glycerol, 0.05% glucose and 0.2% .alpha.-lactose) at
35.degree. C. for 18-20 hours. Cells were harvested by
centrifugation (4,000.times.g, 4.degree. C., 20 min), resuspended
in 50 ml of 10 mM HEPES pH 7.5 (1/20 of the initial volume). The
cells were lysed by sonication (5 pulses of 45 seconds) at 45 W on
ice. The lysates were clarified by centrifugation at 10,000.times.g
for 40 minutes at 4.degree. C. Samples were diluted 5-fold in 50 mM
sodium acetate pH 5.0, stored overnight at 4.degree. C., after
which they were centrifuged at 10,000.times.g for 30 minutes to
clarify, and filtered through 0.45 .mu.m filters. The samples were
loaded onto a 5 ml Capto S sepharose cation exchange column (GE
Healthcare) pre-equilibrated with 50 mM sodium acetate pH 5.0. The
column was washed with 5 column volumes of 50 mM sodium acetate pH
5.0 to wash out unbound protein and a linear gradient of NaCl (0 to
500 mM) was used to elute the protein (over 16 CV) from the column.
Fractions were assayed for .beta.-lactamase activity using Centa
(Calbiochem, Gibbstown, N.J.) or Nitrocefin (EMD Millipore
chemicals, Darmstadt, Germany) as a reporter .beta.-lactamase
substrate for activity in the isolated fractions. Active fractions
were pooled, concentrated and further purified by gel filtration
chromatography on a Superdex 75 prep grade gel filtration column
(GE Healthcare, Piscataway, N.J.) pre-equilibrated in 50 mM Hepes
pH 7.5, 150 mM NaCl. Active fractions were pooled concentrated,
quantitated by BCA protein determination (Thermo Scientific,
Rockford, Ill.), dialyzed into PBS and frozen at -80.degree. C. in
20% glycerol until use.
For Vim-2 metallo .beta.-lactamase, the procedure was identical
with the following exceptions, first the protein was not pH
adjusted to pH 5 with 50 mM sodium acetate, second, the
chromatography step was changed to a 5 ml Q sepharose anion
exchange column pre-equilibrated with 50 mM Hepes pH 7.5, and
elution of the protein was achieved by a linear gradient of NaCl
(0-600 mM). Finally, the VIM-2 purification required a second run
(3.sup.rd step) on the Q sepharose anion exchange column to achieve
acceptable purity (>90%).
.beta.-Lactamase Inhibition.
To determine the level of inhibition of .beta.-lactamase enzymes,
compounds were diluted in PBS at pH 7.4 to yield concentrations
ranging from 100 to 0.00005 .mu.M in 96-well microtiter plates. An
equal volume of diluted enzyme stock was added, and the plates were
incubated at 37.degree. C. for 15 min. Nitrocefin was used as
substrate for p99 AmpC, VIM-2 and OXA-1 and dispensed into each
well at a final concentration of 100 .mu.M. Absorbance at 486 nm
was immediately monitored for 10 min using a Biotek Powerwave XS2
microplate spectrophotometer using the GEN5 softweare package
(Biotek Instruments, Winooski Vt.). In an analogous fashion,
imipenem was used as substrate for Kpc-2 and Cefotaxime was used
for SHV-5, while changes in absorbance upon hydrolysis of the
.beta.-lactam ring were monitored at 300 nm and 260 nm respectively
in UV-transparent 96-well microtiter assay plates. Maximum rates of
hydrolysis were compared to those in control wells (without
inhibitors), and percentages of enzyme inhibition were calculated
for each concentration of inhibitor. The concentration of inhibitor
needed to reduce the initial rate of hydrolysis of substrate by 50%
(IC.sub.50) was calculated as the residual activity of
.beta.-lactamase at 486 nm using GraFit version 7 kinetics software
package (Erithacus Software, Surrey, UK).
Example II: Inhibition of Diverse .beta.-Lactamases by Exemplary
Compounds
Using the methodology described above, examples of the current
invention were evaluated for their ability to inhibit
.beta.-lactamase enzymes from all four Ambler classifications (A
through D). The results of these assays are summarized in Table 2
for representative enzymes across different subtypes (note SHV-5
represents an Ambler Class A Extended Spectrum .beta.-Lactamases,
KPC-2 exemplifies a Class A carbapenemase, P99 represents
chromosomal Class C AmpC, OXA-1 represents a Class D oxacillinase
and VIM-2 represents a class B zinc-dependent
metallo-.beta.-lactamase also possessing carbapenemase activity),
where A represents an IC.sub.50 of 10-100 .mu.M, B represents an
IC.sub.50 of 1 to 10 .mu.M, C represents an IC.sub.50 of 0.1 to 1
.mu.M, and D represents an IC.sub.50 of <0.1 .mu.M. NT=Not
tested.
TABLE-US-00004 TABLE 2 Inhibition of Diverse .beta.-Lactamases by
Exemplary Compounds Class A Class B Class C Class D EXAMPLE SHV-5
KPC-2 VIM-2 AmpC OXA-1 1 D D A D C 2 D C B D C 3 D D B D C 4 D D B
D C 5 B D C D D 6 D C B D C 7 D C B D C 8 A C B D D 9 D D A D D 10
D C B D C 11 D C B D C 12 D D C D D 13 C B A D C 14 C C B D C 15 C
B B D C 16 D C B D D 17 D C B D D 18 C C C D D 19 D C A D D 20 C C
B D D 21 D C B D D 22 C C B D C 23 D D B D D 24 C C A D C 25 D C A
D D 26 C C A D C 27 C C A D C 28 A D A D D 29 B C A C C 30 D D B D
D 31 C D B D D 32 A C A D C 33 D C B D NT 34 D C A C C 35 C C A C C
36 D C B D D 37 C C C D C 38 C B B D NT 39 C D C D D 40 D C C D D
41 D D C D D 42 D D B D NT 43 D D C D D 44 D D A D D 45 D D C D C
46 D C B D C 47 D D C D C 48 D D B D D 49 D D B D D 50 D D B D D 51
B D B D C 52 D D B D D
Example III: In Vitro Antibacterial Assays of R-Lactamase
Inhibition
To determine the ability of test compounds to potentiate the
inhibition of the growth of bacterial strains that produce
beta-lactamase enzymes, classic cell based broth microdilution MIC
assays were employed. Six bacteria strains producing beta-lactamase
enzymes were used: E. coli expressing the Class A Extended Spectrum
Beta-Lactamase (ESBL) CTX-M-15, E. cloacae expressing the Class C
P99, K. pneumoniae expressing the Class A carbapenemase KPC-3, P.
aeruginosa expressing the Class B carbapenemase VIM-2, K.
pneumoniae expressing the class A carbapenemase KPC-2 and the class
B carbapenemase VIM-4, and S. aureus producing the Class A
penicillinase PC-1. The assay was conducted in Cation Adjusted
Mueller Hinton Broth (CAMHB, BD #212322, BD Diagnostic Systems,
Sparks, Md.). Bacteria strains were grown for 3-5 hours in CAMBH
broth. Test compounds (Examples 1-30) were added to a microtiter
plate in 2-fold serial dilutions in CAMHB in a final concentration
range of 32 .mu.g/mL to 0.25 .mu.g/ml. An overlay of CAMHB
containing a Beta-lactam was added to the compounds at a final
static concentration of 4 .mu.g/ml. Ceftazidime (CAZ, Sigma#C3809-1
G, Sigma-Aldrich, St. Louis, Mo.) was used as the partner
antibiotic for E. coli expressing Ambler Class A ESBL CTX-M-15 (MIC
alone>128 .mu.g/ml), and E. cloacae expressing Class C P99 (MIC
alone=128 .mu.g/mL). Meropenem (Mero, USP #1392454, U.S.
Pharmacopeia, Rockville, Md.) was used as the partner antibiotic
for K. pneumoniae expressing Ambler Class A carbapenemase KPC-3
(MIC alone>128 .mu.g/mL), P. aeruginosa expressing Class A
carbapenemase VIM-2 (MIC alone=16 g/mL), and K. pneumoniae
expressing the Ambler Class A carbapenemase KPC-2 and Ambler Class
B carbapenemase VIM-4 (MIC alone=64 .mu.g/mL). Piperacillin (Pip,
Fisher #ICN15626801, MP Biomidicals, Solon, Ohio) was used as the
partner antibiotic for S. aureus producing the Class A
penicillinase PC-1 (MIC alone=64 .mu.g/ml). Titration of test
compounds with MIC readout indicates the concentration of test
article needed to sufficiently inhibit beta-lactamase enzyme
activity and protect the intrinsic antibacterial activity of the
beta-lactam. In addition to the titration of test compounds the
MICs of a panel of control beta-lactams is also tested to ensure
the strains are behaving consistently from test to test. Once the
test compound and antibiotics are added the plates can be
inoculated according to CLSI broth microdilution method. After
inoculation the plates are incubated for 16-20 hours at 37.degree.
C. then the Minimal Inhibitory Concentration (MIC) of the test
compound is determined visually.
Using the methodology described above, examples of the current
invention were evaluated for their ability to inhibit the growth of
.beta.-lactamase-producing bacteria in the presence of a
.beta.-lactam antibiotic.
Representative results are shown in Table 3 where A represents an
MIC>16 g/mL, B represents an MIC between 1 and 16 .mu.g/mL
inclusive, and C represents an MIC of <1 .mu.g/mL. NT=Not
Tested.
Example IV: In Vitro Antibacterial Activity of Exemplary
Compounds
Using the methodology described above in EXAMPLE III, exemplary
compounds for Formula I or Formula Ia were evaluated for their
ability to inhibit the growth of .beta.-lactamase producing
bacteria in the presence of a .beta.-lactam antibiotic.
Representative results are shown in Table 3 where A represents an
MIC of the fixed .beta.-lactam antibiotic in the presence of >32
g/mL of a .beta.-lactamase inhibitor of exemplary Compounds, B
represents the MIC in the presence of between 8 and 32 g/mL of a
.beta.-lactamase inhibitor of exemplary Compounds, and C represents
the MIC in the presence of <4 .mu.g/mL of a .beta.-lactamase
inhibitor of exemplary Compounds. NT=Not Tested.
TABLE-US-00005 TABLE 3 Broad spectrum inhibition of bacterial
growth. MIC of example compounds of the invention in the presence
of a fixed amount (4 (.mu.g/mL) of designated .beta.-lactam
antibiotics ceftazidime (CAZ), meropenem (Mero), Piperacillin
(Pip). MIC (.mu.g/mL) of Examples 1-52 in presence of fixed
.beta.-lactams Fixed Mero Fixed CAZ Carbapenemases ESBLs (Classes A
and B) Fixed Pip (Class A and C) K. P. Penicillinase E. coli E. cl.
K. P. P. aerug. A-1797 S. aureus ESBL4 144200 156319 Ps296 KPC-2
MSSA-7 EXAMPLE CTX-M-15 p99 AmpC KPC-3 VIM-2 VIM-4 PC-1 1 C B N/T A
A C 2 C C B A A C 3 C C C C B C 4 C C C B B C 5 C C C B C B 6 C C C
B B A 7 C C C A A C 8 C C C A A C 9 C C C A A C 10 C C C A C B 11 C
C C A A A 12 C C C B B C 13 C C C B B C 14 C C C B B C 15 C C C C B
C 16 C C C C B C 17 B C B A A C 18 B C C B B A 19 C C B A A B 20 C
C C B A C 21 C C C B A C 22 C C B A A C 23 C C C B B C 24 C C B B B
C 25 C C B B B C 26 C C C C C A 27 C B B B B A 28 C C C C B C 29 C
C C C B C 30 C C C B A A 31 C C C C B C 32 C C A A A C 33 C C B A B
C 34 C C A A A C 35 C C B A B C 36 C C B B B C 37 C C C A B C 38 C
C C B A N/T 39 C C C C B C 40 C C B C B C 41 C C C C C C 42 C C C B
A C 43 C C C C C C 44 C C C A A C 45 C C C C C B 46 C C B A A C 47
C C C C B B 48 C C C C B C 49 C C C B A C 50 C C C C A C 51 C C C C
A C 52 C C C B B C
While preferred embodiments of the present invention have been
shown and described herein, it will be obvious to those skilled in
the art that such embodiments are provided by way of example only.
Numerous variations, changes, and substitutions will now occur to
those skilled in the art without departing from the invention. It
should be understood that various alternatives to the embodiments
of the invention described herein may be employed in practicing the
invention. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
* * * * *
References